Implants using ultrasonic backscatter for sensing physiological conditions

ABSTRACT

Described herein is an implantable device having a sensor configured to detect an amount of an analyte, a pH, a temperature, strain, or a pressure; and an ultrasonic transducer with a length of about 5 mm or less in the longest dimension, configured to receive current modulated based on the analyte amount, the pH, the temperature, or the pressure detected by the sensor, and emit an ultrasonic backscatter based on the received current. The implantable device can be implanted in a subject, such as an animal or a plant. Also described herein are systems including one or more implantable devices and an interrogator comprising one or more ultrasonic transducers configured to transmit ultrasonic waves to the one or more implantable devices or receive ultrasonic backscatter from the one or more implantable devices. Also described are methods of detecting an amount of an analyte, a pH, a temperature, a strain, or a pressure.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. application Ser. No.16/380,944, filed on Apr. 10, 2019, which is a continuation of U.S.application Ser. No. 16/141,930, filed on Sep. 25, 2018, U.S. Pat. No.10,300,310, which is a continuation of U.S. application Ser. No.15/702,301, filed on Sep. 12, 2017, U.S. Pat. No. 10,118,054, which is acontinuation of International Application No. PCT/US2017/041257, filedinternationally on Jul. 7, 2017, which claims priority benefit of U.S.Provisional Application No. 62/359,672, filed on Jul. 7, 2016, all ofwhich are incorporated herein by reference in their entirety for allpurposes.

STATEMENT AS TO FEDERALLY SPONSORED RESEARCH

This invention was made with government support under HR0011-15-2-0006awarded by the Defense Advanced Research Projects Agency. The governmenthas certain rights in the invention.

TECHNICAL FIELD

The present invention relates to implantable devices for sensing andreporting physiological conditions in a subject using ultrasonicbackscatter.

BACKGROUND

A previously known “neural dust” system includes small, implantabledevices (referred to as “neural dust” or “motes”), an implantableultrasound transceiver that communicates with each of the motes usingultrasound transmissions and backscatter transmissions reflected fromthe motes, and an external transceiver that communicates wirelessly withthe implantable ultrasound transceiver. See Seo et al., Neural dust: anultrasonic, low power solution for chronic brain-machine interfaces,arXiv: 1307.2196v1 (Jul. 8, 2013); Seo et al., Model validation ofuntethered, ultrasonic neural dust motes for cortical recording, Journalof Neuroscience Methods, vol. 224, pp. 114-122, available online Aug. 7,2014; and Bertrand et al., Beamforming approaches for untethered,ultrasonic neural dust motes for cortical recording: a simulation study,IEEE EMBC (August 2014). The neural dust system described in thesepapers is used for cortical recording (i.e., the recording of brainelectrical signals). In that application as shown in the papers, themotes are implanted in the brain tissue (cortex), the ultrasoundtransceiver (i.e., an “interrogator”) is implanted below the dura, onthe cortex, and the external transceiver is placed against the head ofthe patient proximate to where the sub-dural ultrasound transceiver isimplanted. This neural dust system is illustrated in FIG. 1.

Careful monitoring of certain physiological conditions in a subject canallow for a better understanding of health and disease prognosis. Forexample, blood sugar monitoring is used to monitor the health of adiabetic patient, and blood oxygenation levels are useful in monitoringcompartment syndrome, cancer, or organ transplants. However, continuousdeep tissue monitoring of certain physiological conditions isimpractical using known technology. What is needed is an implantabledevice for sensing physiological conditions.

SUMMARY OF THE INVENTION

Described herein are implantable devices for sensing physiologicalconditions (such as pH, analyte levels, pressure, strain, ortemperature) in a subject, and reporting the sensed physiologicalconditions using ultrasonic backscatter. Further described are systemsincluding one or more implantable devices and an interrogator. Alsodescribed are methods for sensing physiological conditions and reportingthe sensed physiological conditions using ultrasonic backscatter.

In one aspect, there is provided an implantable device, comprising asensor configured to detect an amount of an analyte, pH, a temperature,strain, or a pressure; and an ultrasonic transducer with a length ofabout 5 mm or less in the longest dimension, configured to receivecurrent modulated based on the analyte amount, the pH, the temperature,the strain, or the pressure detected by the sensor, and emit anultrasonic backscatter based on the received current.

In some embodiments of the implantable device, the ultrasonic transduceris configured to receive ultrasonic waves that power the implantabledevice. In some embodiments, the ultrasonic transducer is configured toreceive ultrasonic waves from an interrogator comprising one or moreultrasonic transducers. In some embodiments, the ultrasonic transduceris a bulk piezoelectric transducer, a piezoelectric micro-machinedultrasonic transducer (PMUT) or a capacitive micro-machined ultrasonictransducer (CMUT).

In some embodiments of the implantable device, the implantable device isabout 5 mm or less in length in the longest dimension. In someembodiments, the volume of the implantable device is about 5 mm³ orless.

In some embodiments, the implantable device is implanted in a subject.In some embodiments, the subject is a human. In some embodiments, thesubject is an animal or a plant.

In some embodiments of the implantable device, the sensor detects theamount of the analyte or pH. In some embodiments, the sensor detects pHor oxygen.

In some embodiments of the implantable device, the sensor is an opticalsensor. In some embodiments, the optical sensor comprises a light sourceand an optical detector. In some embodiments, the optical sensor detectsblood pressure or a pulse. In some embodiments, the optical sensorcomprises a matrix comprising a fluorophore, and wherein fluorescenceintensity or fluorescence lifetime of the fluorophore depends on theamount of the analyte. In some embodiments, the optical sensor isconfigured to perform near-infrared spectroscopy. In some embodiments,the sensor detects glucose.

In some embodiments, the sensor is a potentiometric chemical sensor oran amperometric chemical sensor. In some embodiments, the sensor detectsoxygen, pH, or glucose.

In some embodiments of the implantable device, the sensor is atemperature sensor. In some embodiments, the temperature sensor is athermistor, a thermocouple, or a proportional to absolute temperature(PTAT) circuit. In some embodiments of the implantable device, theimplantable device comprises a bulk piezoelectric ultrasonic transducerand a thermistor.

In some embodiments of the implantable device, the sensor is a pressuresensor. In some embodiments, the pressure sensor ismicroelectromechanical system (MEMS) sensor. In some embodiments, theimplantable device is configured to measure blood pressure or a pulse.

In some embodiments of the implantable device, the sensor is a strainsensor.

In some embodiments of the implantable device, the implantable devicefurther comprises an integrated circuit. In some embodiments, theintegrated circuit comprises one or more of a power circuit, a driverconfigured to provide current to the sensor, a front end configured toreceive a signal from the sensor, or a digital circuit. In someembodiments, the integrated circuit comprises the digital circuit, andwherein the digital circuit is configured to operate a modulationcircuit. In some embodiments, the digital circuit is configured totransmit a digitized signal to the modulation circuit, wherein thedigitized signal is based on the detected amount of the analyte, thetemperature, strain, or the pressure.

In some embodiments of the implantable device, the implanted device isat least partially encapsulated by a biocompatible material.

In some embodiments of the implantable device, the implantable devicefurther comprises a non-responsive reflector.

In some embodiments of the implantable device, the implantable devicecomprises two or more sensors.

Further provided herein is a system comprising one or more implantabledevices and an interrogator comprising one or more ultrasonictransducers configured to transmit ultrasonic waves to the one or moreimplantable devices or receive ultrasonic backscatter from the one ormore implantable devices. In some embodiments, the interrogatorcomprises one or more ultrasonic transducer arrays, wherein eachtransducer array comprises two or more ultrasonic transducers. In someembodiments, the system comprises a plurality of implantable devices. Insome embodiments, the interrogator is configured to beam steertransmitted ultrasonic waves to alternatively focus the transmittedultrasonic waves on a first portion of the plurality of implantabledevices or focus the transmitted ultrasonic waves on a second portion ofthe plurality of implantable devices. In some embodiments, theinterrogator is configured to simultaneously receive ultrasonicbackscatter from at least two implantable devices. In some embodiments,the interrogator is configured to transit ultrasonic waves to theplurality of implantable devices or receive ultrasonic backscatter fromthe plurality of implantable devices using time division multiplexing,spatial multiplexing, or frequency multiplexing. In some embodiments,the interrogator is configured to be wearable by a subject.

In one aspect, there is provided a method of detecting an amount of ananalyte, a pH, a temperature, strain, or a pressure, comprisingreceiving ultrasonic waves that power one or more implantable devicescomprising an ultrasonic transducer with a length of about 5 mm or lessin the longest dimension; converting energy from the ultrasonic wavesinto an electrical current; transmitting the electrical current to asensor configured to measure the amount of the analyte, the pH, thetemperature, strain, or the pressure; modulating the electrical currentbased on the measured amount of the analyte, pH, temperature, strain, orpressure; transducing the modulated electrical current into anultrasonic backscatter that encodes the measured amount of the analyte,pH, temperature, strain, or pressure; and emitting the ultrasonicbackscatter to an interrogator comprising one or more transducerconfigured to receive the ultrasonic backscatter.

In one aspect, there is provided a method of detecting an amount of ananalyte, a pH, a temperature, strain, or a pressure, comprisingreceiving ultrasonic waves that power one or more implantable devicescomprising an ultrasonic transducer with a length of about 5 mm or lessin the longest dimension; converting energy from the ultrasonic wavesinto an electrical current; measuring the amount of the analyte, the pH,the temperature, the strain, or the pressure using a sensor; modulatingthe electrical current based on the measured amount of the analyte, pH,temperature, the strain, or pressure; transducing the modulatedelectrical current into an ultrasonic backscatter that encodes themeasured amount of the analyte, pH, temperature, strain, or pressure;and emitting the ultrasonic backscatter to an interrogator comprisingone or more transducer configured to receive the ultrasonic backscatter.

In some embodiments of the above-described methods, the method furthercomprises receiving the ultrasonic backscatter using the interrogator.In some embodiments, the method further comprises transmitting theultrasonic waves using the interrogator configured to transmit theultrasonic waves. In some embodiments, the ultrasonic waves aretransmitted in two or more pulses.

In some embodiments of the above-described methods, the method furthercomprises analyzing the ultrasonic backscatter to determine the measuredamount of the analyte, pH, temperature, strain, or pressure. In someembodiments of the above-described methods, the one or more implantabledevices are implanted on, within, or proximal to a blood vessel, animplanted organ, a tumor, or a site of infection.

In some embodiments of the above-described methods, the method furthercomprises emitting light and detecting fluorescence intensity orfluorescence lifetime, wherein the fluorescence intensity orfluorescence lifetime depends on the amount of the analyte or the pH. Insome embodiments, the method comprises determining a phase shift betweenoscillating emitted light and detected fluorescence is determined,wherein the phase shift depends on the amount of the analyte or the pH.In some embodiments, the method comprises determining a fluorescentlifetime for the detected fluorescence resulting from pulsed oroscillating emitted light.

In some embodiments of the above-described methods, the method furthercomprises determining a location of the one or more implantable devicesrelative to the interrogator.

In some embodiments of the above-described methods, the method furthercomprises detecting movement of the one or more implantable devices.

In some embodiments of the above-described methods, the method furthercomprises implanting the implantable device in a subject. In someembodiments, the subject is an animal or a plant. In some embodiments,the subject is a human.

In some embodiments of the above-described methods, the ultrasonicbackscatter encodes a digitized signal.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a schematic of a neural dust system, including an externaltransceiver, a sub-dural interrogator, and a neural dust mote, asdescribed in Seo et al., Neural dust: an ultrasonic, low power solutionfor chronic brain-machine interfaces, arXiv: 1307.2196v1 (Jul. 8, 2013).

FIG. 2A is a block diagram of an exemplary interrogator for a systemdescribed herein. The illustrated interrogator includes an ultrasonictransducer array comprising a plurality of ultrasonic transducers. Eachof the ultrasonic transducers in the array is operated by a channel,which includes a switch to alternatively configure the transducer toreceive or transmit ultrasonic waves. FIG. 2B is a schematic of anotherexemplary interrogator for a system described herein. The illustratedinterrogator includes two ultrasonic transducer arrays, with eachultrasonic transducer array including a plurality of ultrasonictransducers. The interrogator also includes an integrated circuit (whichcan include a digital circuit, which can include a processor). Theintegrated circuit is connected to a user interface (which can include adisplay, keyboard, buttons, etc.), a storage medium (i.e., anon-transitory memory), an input/output (which may be wireless, such asa Bluetooth), and a power supply (such as a battery).

FIG. 3A shows a block diagram of an exemplary interrogator that can beworn by a subject. The interrogator includes a wireless communicationsystem (a Bluetooth radio, in the illustration), which can be used tocommunicate with a computer system. FIG. 3B shows an exploded view of awearable interrogator. The interrogator includes a battery, a wirelesscommunication system, and a transducer array. FIG. 3C shows the wearableinterrogator shown in FIG. 3B fully assembled with a harness forattachment to a subject. FIG. 3D illustrates the wearable interrogatorattached a subject, namely a rodent (although could be any type ofanimal, such as a human, dog, cat, horse, cow, pig, sheep, goat,chicken, monkey, rat or mouse). The interrogator includes a transducerarray, which is fixed to the body of the subject by an adhesive. FIG. 3Eillustrates a cross-section of the transducer array of the interrogatorshown in FIGS. 3A-D.

FIG. 4 provides a schematic showing the communication between atransducer from an interrogator and an implantable device having aminiaturized ultrasonic transducer. The interrogator transmitsultrasonic waves to the implantable device, and the miniaturizedultrasonic transducer emits ultrasonic backscatter modulated by thesensor. The backscatter is then received by the interrogator.

FIG. 5A shows a series of cycles of ultrasonic wave pulses emitted by aninterrogator. Upon receiving a trigger from the interrogator (e.g., anFPGA), the transceiver board of the interrogator generates a series oftransmit pulses. At the end of the transmit cycle, the switch on theASIC disconnects the transmit module and connects the receive module.The cycles have a frequency of every 100 microseconds. FIG. 5B shows azoomed-in view of the transmit pulse sequence (i.e., one cycle) shown inFIG. 5A, with the cycle having six pulses of ultrasonic waves at 1.85MHz, the pulses recurring every 540 nanoseconds. FIG. 5C showsultrasonic backscatter emitted by an implantable device. The ultrasonicbackscatter reaches the transducer of the interrogator approximately2t_(Rayleigh). FIG. 5D shows a zoomed-in view of the ultrasonicbackscatter, which can be analyzed. Analysis of the ultrasonicbackscatter can include filtering, rectifying and integrating theultrasonic backscatter waves. FIG. 5E shows a zoomed in view of thefiltered ultrasonic backscatter waves. The backscatter wave includesresponsive regions, which are responsive to changes in impedance to theminiaturized ultrasonic transducer, and non-responsive regions that arenot responsive to changes in impedance to the miniaturized ultrasonictransducer.

FIG. 6A illustrates a schematic of an implantable device with aminiaturized ultrasonic transducer and a sensor. FIG. 6B illustrates aschematic of an implantable device with a miniaturized ultrasonictransducer, an integrated circuit, and a sensor.

FIG. 7A illustrates a schematic of an exemplary implantable deviceincluding a miniaturized ultrasonic transducer and an ASIC on a printedcircuit board (PCB). FIG. 7B illustrates a schematic of anotherexemplary implantable device including a miniaturized ultrasonictransducer and an ASIC on a printed circuit board (PCB).

FIG. 8A illustrates one embodiment of an ASIC attached to a miniaturizedultrasonic transducer for an implantable device. FIG. 8B illustratesanother embodiment of an integrated circuit attached to a miniaturizedultrasonic transducer for an implantable device.

FIG. 9A illustrates backscatter communication of the implantable devicesensor to an external transceiver based on intensity modulation of lightin tissue from an optical emitter. The sensor on the implantable devicecan be an optical filter-enhanced sensor. FIG. 9B illustrates alternatepulsing of monochromatic light using an array of elements emitting lightof varying wavelengths right) for the implementation of NIR multiplewavelength spectrophotometry using an optical sensor. FIG. 9Cillustrates an implantable device having an optical sensor, including alight source and an optical detector. The sensor includes an integratedoptical emitter.

FIG. 10A illustrates a pulse of light emitted by a light source and theresulting fluorescent decay detected by an optical detector after thelight excites a fluorophore in a matrix in an optical sensor. FIG. 10Billustrates the phase shift between an oscillating light emitted by alight source and the resulting fluorescent lifetime detected by anoptical detector after the light excites a fluorophore in a matrix in anoptical sensor. FIG. 10C illustrates a schematic of an exemplary opticalsensor for detecting the phase shift shown in FIG. 10B.

FIG. 11A illustrates a schematic of one embodiment of an implantabledevice with a miniaturized ultrasonic transducer, an integrated circuit,and an optical sensor. FIG. 11B illustrates another schematic of oneembodiment of an implantable device with a miniaturized ultrasonictransducer, an integrated circuit, and an optical sensor.

FIG. 12A illustrates a schematic of one embodiment of an implantabledevice with a miniaturized ultrasonic transducer and a temperaturesensor. FIG. 12B illustrates a schematic of one embodiment of animplantable device with a miniaturized ultrasonic transducer, anintegrated circuit, and a temperature sensor.

FIG. 13A illustrates a schematic of one embodiment of an implantabledevice with a miniaturized ultrasonic transducer and a pressure sensor.FIG. 13B illustrates a schematic of one embodiment of an implantabledevice with a miniaturized ultrasonic transducer, an integrated circuit,and a pressure sensor.

FIG. 14 illustrates a method of manufacturing an implantable devicedescribed herein.

FIG. 15 is a flowchart for a method of encapsulating an implantabledevice with amorphous silicon carbide.

FIG. 16A shows different geometries of vias used to connect componentsof the implantable device. FIG. 16B shows a serpentine traceconfiguration for deformable interconnects.

FIG. 17 shows the relationship between time and temperature for curingsilver epoxy, an exemplary material for attaching wirebonds during themanufacture of the implantable device.

FIG. 18 illustrates a schematic for encapsulating an implantable devicein silicon carbide.

FIG. 19 shows an assembly prototype schematic and PCB.

FIG. 20A-E show processing steps to ensure that the desired miniaturizedultrasonic transducer (PZT) dimension is assembled on the PCB. At FIG.20A, epoxy solder paste is dispensed onto the board. At FIG. 20B, apiezoelectric material is attached to the PCB. At FIG. 20C, thepiezoelectric material is diced to form a bulk piezoelectric ultrasonictransducer of the desired size. At FIG. 20D, the ultrasonic transduceris wirebonded to the PCB. At FIG. 20E, the PCB and ultrasonic transduceris encapsulated in PDMS.

FIG. 21 shows a schematic for measuring electrical impedance with avector network analyzer (VNA).

FIG. 22A shows that the measured power transfer efficiency at variousbulk piezoelectric ultrasonic transducer sizes matches simulatedbehavior. FIG. 22B shows that the measured impedance spectroscopy of aPZT crystal matches a simulation. FIG. 22C show that the frequencyresponse of harvested power of the miniaturized ultrasonic transducer isapproximately 6.1 MHz.

FIG. 23 is a schematic of an exemplary ultrasonic transducer that can beused as part of an interrogator.

FIG. 24 is a schematic of a setup for acoustic characterization with acalibrated ultrasonic transducer for power delivery verification. Theultrasonic wave receiver is separate from the ultrasonic wavetransmitter.

FIG. 25A shows the output power of a 5 MHz transducer as the hydrophoneis moved away from the transducer's surface. FIG. 25B shows that thede-rated peak is shifted to the left in relation to the water peak.

FIG. 26A shows the XZ cross-section of the transducer output,illustrating a Rayleigh distance and a clear transition from thenear-field to far-field propagation. FIG. 26B shows the XY beamcross-section showing a 6 dB bandwidth of the beam at 2.2 mm.

FIG. 27A shows a focused 2D beam pattern from a transducer array in theXY plane. The measured beam approximates the simulated beam in both theX and Y dimensions. FIG. 27B shows the delay time applied to eachtransducer element in the ultrasonic transducer array. FIG. 27C shows asimulated 2D XZ cross-sectional beam pattern.

FIG. 28A shows beam steering of an ultrasonic wave beam transmitted froma transducer array. Underneath each beam pattern is the delay for eachtransducer in the array to obtain the measured beam pattern, as shown inFIG. 28B. FIG. 28C shows the 1D beam pattern in the X-axis for each beampattern shown in FIG. 28A. The measured beam pattern closelyapproximates the simulated beam pattern.

FIG. 29 shows a simulated scaling of miniaturized ultrasonic transducerlink efficiency and received power at 5 mm in tissue.

FIG. 30A shows the de-rated normalized peak pressure as a function ofdistance from the surface of an exemplary transducer has a de-ratedfocus at about 8.9 mm at 1.85 MHz. FIG. 30B shows the XY cross-sectionalbeam patterns and the corresponding 1D voltage plot at y=0 atnear-field, Rayleigh distance, and far-field. The patterns show the beamfocusing at the Rayleigh distance. FIG. 30C shows that the transducer'soutput pressure was a linear function of input voltage (up to 32 Vpeak-to-peak).

FIG. 31A (duplicate of FIG. 5E shown in different context) shows examplebackscatter waveform showing different regions of backscatter. Thebackscatter waveform is found flanked (in time) by regions whichcorrespond to reflections arising from non-responsive regions; thesecorrespond to reflected waveforms from other implantable devicecomponents. The measurement from the non-responsive regions (which donot encode biological data) can be used as a reference. As a result oftaking this differential measurement, any movements of the entirestructure relative to the external transducer during the experiment canbe subtracted out. FIG. 31B is a calibration curve obtained from thecustom water tank setup, which show the noise flor of 0.18 mV_(rms).FIG. 31C shows the effect of noise floor as a function of lateralmisalignment following the beam pattern power fall-off. FIG. 31D shows a1-D plot of the transducer's off-axis voltage and power drop off at y=0at Rayleigh distance. FIG. 31E shows a plot of drop in the effectivenoise floor as a function of angular misalignment. Angular misalignmentresults in a skewed beam pattern: ellipsoidal as opposed to circular.This increases the radius of focal spot (spreading energy out over alarger area); the distortion of the focal spot relaxes the constraint onmisalignment.

FIG. 32A shows ultrasonic backscatter from an implantable device, withthe implantable device implanted inn ultrasound coupling gel used tomimic tissue. The backscatter includes a transmit feedthrough andring-down centered at 26 microseconds, and the miniaturized ultrasonictransducer backscatter centered around 47 microseconds. FIG. 32B shows aclose-up on the backscatter region from the miniaturized ultrasonictransducer (the responsive region), which shows amplitude modulation asa result of a signal input to the implantable device.

FIG. 33 shows digital data corresponding to ASCII characters ‘helloworld’ wirelessly ready from the implantable device through pulseamplitude backscatter modulation with unipolar encoding.

FIG. 34A shows an illustration of an implantable device with aminiaturized ultrasonic bulk piezoelectric transducer and a thermistor.A non-responsive reflector is attached to the implantable device toreflect non-responsive backscatter waves. FIG. 34B shows two implantabledevices, each with a miniaturized ultrasonic bulk piezoelectrictransducer and a thermistor. The top device has an approximate volume of0.118 mm³, and the bottom device has an approximate volume of 1.45 mm³.

FIG. 35 shows a cross-sectional rendering of an experimental design forbackscatter characterization of individual implantable devices withtemperature sensors. A sheet of 0.5 mil thick PET was glued onto the toppiece of the water tank, which serves to contain the water within thetank while thermally isolating the implantable device.

FIG. 36 shows ultrasonic backscatter from an implantable device with aminiaturized ultrasonic bulk piezoelectric transducer, a thermistor, anda non-responsive reflector at high temperature and low temperature. Theimplantable device was interrogated at 3.35 MHz. Region [1] correspondsto the contribution of the non-responsive reflector, whereas region [2]corresponds to the contribution of the thermally modulated transducer onthe implantable device. The temperature dependent changes can be seen asan increase in signal amplitude (and thus area under the curve forrectified signals) in region [2]. Region [1] does not exhibit suchchanges.

FIG. 37 shows mean normalized area under the curve for the ultrasonicbackscatter of a single implantable device with a thermistor as afunction of temperature from 34.5° C. to 44.5° C. Temperature wasincreased at 0.5° C. intervals, and ten collected backscatter waveformsareas were normalized to those at 44.5° C. Error bars represent standarddeviation of the ten measurements at each temperature.

DETAILED DESCRIPTION OF THE INVENTION

The implantable device described herein includes a miniaturizedultrasonic transducer (such as a miniaturized piezoelectric transducer)and a physiological sensor. The miniaturized ultrasonic transducerreceives ultrasonic energy from an interrogator (which may be externalor implanted), which powers the implantable device. The interrogatorincludes a transmitter and a receiver (which may be integrated into acombined transceiver), and the transmitter and the receiver may be onthe same component or different components. The physiological sensordetects a physiological condition (such as pressure, temperature,strain, pressure, or an amount of one or more analytes), and generatesan analog or digital electrical signal. Mechanical energy from theultrasonic waves transmitted by the interrogator vibrates theminiaturized ultrasonic transducer on the implantable device, whichgenerates an electrical current. The current flowing through theminiaturized ultrasonic transducer is modulated by the electricalcircuitry in the implantable device based on the detected physiologicalcondition. The miniaturized ultrasonic transducer emits an ultrasonicbackscatter communicating information indicative of the sensedphysiological condition, which is detected by the receiver components ofthe interrogator.

A significant advantage of the implantable device is the ability todetect one or more physiological conditions in deep tissue while beingwirelessly powered, and to have those physiological conditionswirelessly transmitted to an interrogator, which can be external orrelay the information to an external component. Thus, the implantabledevices can remain in a subject for an extended period of time withoutneeding to charge a battery or retrieve information stored on thedevice. These advantages, in turn, allow the device to be smaller andless expensive to manufacture. In another advantage, use of ultrasoundallows for the relative time for data communication to be related todistance, which can aid in determining location or movement of theimplantable device in real time.

Electromagnetic (EM) power transfer is not practical for powering smallimplantable devices due to power attenuation through tissue and therelatively large apertures (e.g. antennas or coils) required to capturesuch energy. See, for example, Seo et al., Neural dust: an ultrasonic,low power solution for chronic brain-machine interfaces, arXiv paper(July 2013). Use of EM to supply sufficient power to an implanted devicewould either require a shallow depth of the implant or would requireexcessive heating of the tissue to pass the EM waves through the tissueto reach the implantable device. In contrast to EM, ultrasonic powertransfer provides low power attenuation in tissue due to the relativelylow absorption of ultrasonic energy by tissue and the shorter wavelengthof the ultrasonic waves (as compared to electromagnetic waves).

Ultrasonic transducers have found application in various disciplinesincluding imaging, high intensity focused ultrasound (HIFU),nondestructive testing of materials, communication and power deliverythrough steel walls, underwater communications, transcutaneous powerdelivery, and energy harvesting. See, e.g., Ishida et al., InsolePedometer with Piezoelectric Energy Harvester and 2 V Organic Circuits,IEEE J. Solid-State Circuits, vol. 48, no. 1, pp. 255-264 (2013); Wonget al., Advantages of Capacitive Micromachined Ultrasonics Transducers(CMUTs) for High Intensity Focused Ultrasound (HIFU), IEEE UltrasonicsSymposium, pp. 1313-1316 (2007); Ozeri et al., Ultrasonic TranscutaneousEnergy Transfer for Powering Implanted Devices, Ultrasonics, vol. 50,no. 6, pp. 556-566 (2010); and Richards et al., Efficiency of EnergyConversion for Devices Containing a Piezoelectric Component, J.Micromech. Microeng., vol. 14, pp. 717-721 (2004). Unlikeelectromagnetics, using ultrasound as an energy transmission modalitynever entered into widespread consumer application and was oftenoverlooked because the efficiency of electromagnetics for shortdistances and large apertures is superior. However, at the scale of theimplantable devices discussed herein and in tissue, the low acousticvelocity allows operation at dramatically lower frequencies, and theacoustic loss in tissue is generally substantially smaller than theattenuation of electromagnetics in tissue.

The relatively low acoustic velocity of ultrasound results insubstantially reduced wavelength compared to EM. Thus, for the sametransmission distance, ultrasonic systems are much more likely tooperate in the far-field, and hence obtain larger spatial coverage thanan EM transmitter. Further, the acoustic loss in tissue is fundamentallysmaller than the attenuation of electromagnetics in tissue becauseacoustic transmission relies on compression and rarefaction of thetissue rather than time-varying electric/magnetic fields that generatedisplacement currents on the surface of the tissue.

It has been found that ultrasonic waves can be used to power andcommunicate with miniaturized implantable devices containing aminiaturized ultrasonic transducer (such as a bulk piezoelectric, aPMUT, or a CMUT) and a sensor.

The implantable devices described herein can be implanted in or used ina subject (e.g., an animal or a plant). In some embodiments, the subjectis a mammal. Exemplary subjects include a rodent (such as a mouse, rat,or guinea pig), cat, dog, chicken, pig, cow, horse, sheep, rabbit, etc.In some embodiments, the subject is a human. The implantable devices canalso be implanted in plants, such as agricultural plants, to measurephysiological conditions.

Definitions

As used herein, the singular forms “a,” “an,” and “the” include theplural reference unless the context clearly dictates otherwise.

Reference to “about” a value or parameter herein includes (anddescribes) variations that are directed to that value or parameter perse. For example, description referring to “about X” includes descriptionof “X”.

The term “miniaturized” refers to any material or component about 5millimeters or less (such as about 4 mm or less, about 3 mm or less,about 2 mm or less, about 1 mm or less, or about 0.5 mm or less) inlength in the longest dimension. In certain embodiments, a“miniaturized” material or component has a longest dimension of about0.1 mm to about 5 mm (such as about 0.2 mm to about 5 mm, about 0.5 mmto about 5 mm, about 1 mm to about 5 mm, about 2 mm to about 5 mm, about3 mm to about 5 mm, or about 4 mm to about 5 mm) in length.“Miniaturized” can also refer to any material or component with a volumeof about 5 mm³ or less (such as about 4 mm³ or less, 3 mm³ or less, 2mm³ or less, or 1 mm³ or less). In certain embodiments, a “miniaturized”material or component has a volume of about 0.5 mm³ to about 5 mm³,about 1 mm³ to about 5 mm³, about 2 mm³ to about 5 mm³, about 3 mm³ toabout 5 mm³, or about 4 mm³ to about 5 mm³.

A “piezoelectric transducer” is a type of ultrasonic transceivercomprising piezoelectric material. The piezoelectric material may be acrystal, a ceramic, a polymer, or any other natural or syntheticpiezoelectric material.

A “non-responsive” ultrasonic wave is an ultrasonic wave with areflectivity independent of a detected signal. A “non-responsivereflector” is a component of an implantable device that reflectsultrasonic waves such that the reflected waveform is independent of thedetected signal.

It is understood that aspects and variations of the invention describedherein include “consisting” and/or “consisting essentially of” aspectsand variations.

Where a range of values is provided, it is to be understood that eachintervening value between the upper and lower limit of that range, andany other stated or intervening value in that stated range, isencompassed within the scope of the present disclosure. Where the statedrange includes upper or lower limits, ranges excluding either of thoseincluded limits are also included in the present disclosure.

It is to be understood that one, some or all of the properties of thevarious embodiments described herein may be combined to form otherembodiments of the present invention. The section headings used hereinare for organizational purposes only and are not to be construed aslimiting the subject matter described.

Features and preferences described above in relation to “embodiments”are distinct preferences and are not limited only to that particularembodiment; they may be freely combined with features from otherembodiments, where technically feasible, and may form preferredcombinations of features.

The description is presented to enable one of ordinary skill in the artto make and use the invention and is provided in the context of a patentapplication and its requirements. Various modifications to the describedembodiments will be readily apparent to those persons skilled in the artand the generic principles herein may be applied to other embodiments.Thus, the present invention is not intended to be limited to theembodiment shown but is to be accorded the widest scope consistent withthe principles and features described herein. Further, sectionalheadings are provide for organizational purposes and are not to beconsidered limiting. Finally, the entire disclosure of the patents andpublications referred in this application are hereby incorporated hereinby reference for all purposes.

Interrogator

The interrogator can wirelessly communicate with one or more implantabledevices using ultrasonic waves, which are used to power and/or operatethe implantable device. The interrogator can further receive ultrasonicbackscatter from the implantable device, which encodes informationindicative of the sensed physiological condition. The interrogatorincludes one or more ultrasonic transducers, which can operate as anultrasonic transmitter and/or an ultrasonic receiver (or as atransceiver, which can be configured to alternatively transmit orreceive the ultrasonic waves). The one or more transducers can bearranged as a transducer array, and the interrogator can optionallyinclude one or more transducer arrays. In some embodiments, theultrasound transmitting function is separated from the ultrasoundreceiving function on separate devices. That is, optionally, theinterrogator comprises a first device that transmits ultrasonic waves tothe implantable device, and a second device that receives ultrasonicbackscatter from the implantable device. In some embodiments, thetransducers in the array can have regular spacing, irregular spacing, orbe sparsely placed. In some embodiments the array is flexible. In someembodiments the array is planar, and in some embodiments the array isnon-planar.

An exemplary interrogator is shown in FIG. 2A. The illustratedinterrogator shows a transducer array with a plurality of ultrasonictransducers. In some embodiments, the transducer array includes 1 ormore, 2 or more, 3 or more, 5 or more, 7 or more, 10 or more, 15 ormore, 20 or more, 25 or more, 50 or more, 100 or more 250 or more, 500or more, 1000 or more, 2500 or more, 5000 or more, or 10,000 or moretransducers. In some embodiments, the transducer array includes 100,000or fewer, 50,000 or fewer, 25,000 or fewer, 10,000 or fewer, 5000 orfewer, 2500 or fewer, 1000 or fewer, 500 or fewer, 200 or fewer, 150 orfewer, 100 or fewer, 90 or fewer, 80 or fewer, 70 or fewer, 60 or fewer,50 or fewer, 40 or fewer, 30 or fewer, 25 or fewer, 20 or fewer, 15 orfewer, 10 or fewer, 7 or fewer or 5 or fewer transducers. The transducerarray can be, for example a chip comprising 50 or more ultrasonictransducer pixels. The interrogator shown in FIG. 2A illustrates asingle transducer array; however the interrogator can include 1 or more,2 or more, or 3 or more separate arrays. In some embodiments, theinterrogator includes 10 or fewer transducer arrays (such as 9, 8, 7, 6,5, 4, 3, 2, or 1 transducer arrays). The separate arrays, for example,can be placed at different points of a subject, and can communicate tothe same or different implantable devices. In some embodiments, thearrays are located on opposite sides of an implantable device. Theinterrogator can include an ASIC, which includes a channel for eachtransducer in the transducer array. In some embodiments, the channelincludes a switch (indicated in FIG. 2A by “T/Rx”). The switch canalternatively configure the transducer connected to the channel totransmit ultrasonic waves or receive ultrasonic waves. The switch canisolate the ultrasound receiving circuit from the higher voltageultrasound transmitting circuit. In some embodiments, the transducerconnected to the channel is configured only to receive or only totransmit ultrasonic waves, and the switch is optionally omitted from thechannel. The channel can include a delay control, which operates tocontrol the transmitted ultrasonic waves. The delay control can control,for example, the phase shift, time delay, pulse frequency and/or waveshape (including amplitude and wavelength). The delay control can beconnected to a level shifter, which shifts input pulses from the delaycontrol to a higher voltage used by the transducer to transmit theultrasonic waves. In some embodiments, the data representing the waveshape and frequency for each channel can be stored in a ‘wave table’.This allows the transmit waveform on each channel to be different. Then,delay control and level shifters can be used to ‘stream’ out this datato the actual transmit signals to the transducer array. In someembodiments, the transmit waveform for each channel can be produceddirectly by a high-speed serial output of a microcontroller or otherdigital system and sent to the transducer element through a levelshifter or high-voltage amplifier. In some embodiments, the ASICincludes a charge pump (illustrated in FIG. 2A) to convert a firstvoltage supplied to the ASIC to a higher second voltage, which isapplied to the channel. The channels can be controlled by a controller,such as a digital controller, which operates the delay control. In theultrasound receiving circuit, the received ultrasonic waves areconverted to current by the transducers (set in a receiving mode), whichis transmitted to a data capture circuit. In some embodiments, anamplifier, an analog-to-digital converter (ADC), avariable-gain-amplifier, or a time-gain-controlledvariable-gain-amplifier which compensates for tissue loss, and/or a bandpass filter is included in the receiving circuit. The ASIC can drawpower from a power supply, such as a battery (which is preferred for awearable embodiment of the interrogator). In the embodiment illustratedin FIG. 2A, a 1.8V supply is provided to the ASIC, which is increased bythe charge pump to 32V, although any suitable voltage can be used. Insome embodiments, the interrogator includes a processor and or anon-transitory computer readable memory. In some embodiments, thechannel described above does not include a T/Rx switch but insteadcontains independent Tx (transmit) and Rx (receive) with a high-voltageRx (receiver circuit) in the form of a low noise amplifier with goodsaturation recovery. In some embodiments, the T/Rx circuit includes acirculator. In some embodiments, the transducer array contains moretransducer elements than processing channels in the interrogatortransmit/receive circuitry, with a multiplexer choosing different setsof transmitting elements for each pulse. For example, 64 transmitreceive channels connected via a 3:1 multiplexer to 192 physicaltransducer elements—with only 64 transducer elements active on a givenpulse.

FIG. 2B illustrates another embodiment of interrogator. As shown in FIG.2B, the interrogator includes one or more transducers 202. Eachtransducer 202 is connected to a transmitter/receiver switch 204, whichcan alternatively configure the transducer to transmit or receiveultrasonic waves. The transmitter/receiver switch is connected to aprocessor 206 (such as a central processing unit (CPU), a customdedicated processor ASIC, a field programmable gate array (FPGA),microcontroller unit (MCU), or a graphics processing unit (GPU)). Insome embodiments, the interrogator further includes an analog-digitalconverter (ADC) or digital-to-analog converter (DAC). The interrogatorcan also include a user interface (such as a display, one or morebuttons to control the interrogator, etc.), a memory, a power supply(such as a battery), and/or an input/output port (which may be wired orwireless).

In some embodiments, the interrogator is implantable. An implantedinterrogator may be preferred when the implantable devices are implantedin a region blocked by a barrier that does not easily transmitultrasonic waves. For example, the interrogator can be implantedsubcranially, either subdurally or supradurally. A subcranialinterrogator can communicate with implantable devices that are implantedin the brain. Since ultrasonic waves are impeded by the skull, theimplanted subcranial interrogator allows for communication with theimplantable devices implanted in the brain. In another example, animplantable interrogator can be implanted as part of, behind or withinanother implanted device, such as a bone plate. The implantedinterrogator can communicate with an external device, for example by EMor RF signals.

In some embodiments, the interrogator is external (i.e., not implanted).By way of example, the external interrogator can be a wearable, whichmay be fixed to the body by a strap or adhesive. In another example, theexternal interrogator can be a wand, which may be held by a user (suchas a healthcare professional). In some embodiments, the interrogator canbe held to the body via suture, simple surface tension, a clothing-basedfixation device such as a cloth wrap, a sleeve, an elastic band, or bysub-cutaneous fixation. The transducer or transducer array of theinterrogator may be positioned separately from the rest of thetransducer. For example, the transducer array can be fixed to the skinof a subject at a first location (such as proximal to one or moreimplanted devices), and the rest of the interrogator may be located at asecond location, with a wire tethering the transducer or transducerarray to the rest of the interrogator. FIG. 3A-E shows an example of awearable external interrogator. FIG. 3A shows a block diagram of theinterrogator, which includes a transducer array comprising a pluralityof transducers, an ASIC comprising a channel for each transducer in thetransducer array, a battery (lithium polymer (LiPo) battery, in theillustrated example), and a wireless communication system (such as aBluetooth system). FIG. 3B illustrates an exploded view of a wearableinterrogator, including a printed circuit board (PCB) 302, whichincludes the ASIC, a wireless communication system 304, a battery 306,an ultrasonic transducer array 308, and a wire 310 tethering theultrasonic transducer array 308 to the ASIC. FIG. 3C shows the wearableinterrogator 312 shown in FIG. 3B with a harness 314, which can be usedto attach the interrogator to a subject. FIG. 3D shows the assembledinterrogator 316 attached to a subject, with the transducer array 308attached at a first location, and the rest of the interrogator attachedto a second location. FIG. 3E shows a cross-section schematic of anexemplary ultrasonic transducer array 308, which includes a circuitboard 318, vias 320 attaching each transducer 322 to the circuit board318, a metalized polyester film 324, and an absorptive backing layer326. The metalized polyester film 324 can provide a common ground andacoustic matching for the transducers, while the absorptive backinglayer 326 (such as tungsten powder filled polyurethane) can reduceringing of the individual transducers.

The specific design of the transducer array depends on the desiredpenetration depth, aperture size, and size of the individual transducerswithin the array. The Rayleigh distance, R, of the transducer array iscomputed as:

${R = {\frac{D^{2} - \lambda^{2}}{4\lambda} \approx \frac{D^{2}}{4\lambda}}},{D^{2}\lambda^{2}}$

where D is the size of the aperture and λ is the wavelength ofultrasound in the propagation medium (i.e., the tissue). As understoodin the art, the Rayleigh distance is the distance at which the beamradiated by the array is fully formed. That is, the pressure filedconverges to a natural focus at the Rayleigh distance in order tomaximize the received power. Therefore, in some embodiments, theimplantable device is approximately the same distance from thetransducer array as the Rayleigh distance.

The individual transducers in a transducer array can be modulated tocontrol the Raleigh distance and the position of the beam of ultrasonicwaves emitted by the transducer array through a process of beamformingor beam steering. Techniques such as linearly constrained minimumvariance (LCMV) beamforming can be used to communicate a plurality ofimplantable devices with an external ultrasonic transceiver. See, forexample, Bertrand et al., Beamforming Approaches for Untethered,Ultrasonic Neural Dust Motes for Cortical Recording: a Simulation Study,IEEE EMBC (August 2014). In some embodiments, beam steering is performedby adjusting the power or phase of the ultrasonic waves emitted by thetransducers in an array.

In some embodiments, the interrogator includes one or more ofinstructions for beam steering ultrasonic waves using one or moretransducers, instructions for determining the relative location of oneor more implantable devices, instructions for monitoring the relativemovement of one or more implantable devices, instructions for recordingthe relative movement of one or more implantable devices, andinstructions for deconvoluting backscatter from a plurality ofimplantable devices.

Communication Between an Implantable Device and an Interrogator

The implantable device and the interrogator wirelessly communicate witheach other using ultrasonic waves. The implantable device receivesultrasonic waves from the interrogator through a miniaturized ultrasonictransducer on the implantable device. Vibrations of the miniaturizedultrasonic transducer on the implantable device generate a voltageacross the electric terminals of the transducer and a current flowsthrough the device, including the sensor and/or, if present, the ASIC.Depending on the physiological condition detected by the sensor,information relating to the physiological condition can alter thecurrent, which in turns modulates the backscatter from the miniaturizedultrasonic transducer. The sensor system (optionally including an ASIC)presents electrical impedance to the electric terminals on thetransducer. If this impedance changes, the mechanical impedance of thetransducer (as seen from outside the device) changes, resulting inchanges in backscatter. Thus, the sensor system modulates the electricalimpedance presented to the transducer to effect backscattercommunication. The backscatter is then received by an externalultrasonic transceiver (which may be the same or different from theexternal ultrasonic transceiver that transmitted the initial ultrasonicwaves). The information from the sensor can thus be encoded by changesin amplitude, frequency, or phase of the backscattered ultrasound waves.FIG. 4 illustrates an interrogator in communication with an implantabledevice. The external ultrasonic transceiver emits ultrasonic waves(“carrier waves”), which can pass through tissue. The carrier wavescause mechanical vibrations on the miniaturized ultrasonic transducer(e.g., a miniaturized bulk piezoelectric transducer, a PMUT, or a CMUT).A voltage across the miniaturized ultrasonic transducer is generated,which imparts a current flowing through a sensor on the implantabledevice. In some embodiments, the implantable device includes an ASIC,and current flows from the miniaturized ultrasonic transducer, throughthe ASIC, to the radiation detector, back to the ASIC, and returns tothe miniaturized ultrasonic transducer. The current flowing through theminiaturized ultrasonic transducer causes the transducer on theimplantable device to emit backscatter ultrasonic waves. The currentflowing through the miniaturized ultrasonic transducer changes theamplitude, frequency, and/or phase of the backscatter ultrasonic waveemitted or reflected from the ultrasonic transducer. Since thephysiological condition affects the current returning to the ASIC and/orthe miniaturized ultrasonic transducer, the backscatter waves encodeinformation relating to the physiological condition. The backscatterwaves can be detected by the interrogator, and can be deciphered todetermine the physiological condition or a change in the physiologicalcondition.

Communication between the interrogator and the implantable device canuse a pulse-echo method of transmitting and receiving ultrasonic waves.In the pulse-echo method, the interrogPator transmits a series ofinterrogation pulses at a predetermined frequency, and then receivesbackscatter echoes from the implanted device. In some embodiments, thepulses are about 200 nanoseconds (ns) to about 1000 ns in length (suchas about 300 ns to about 800 ns in length, about 400 ns to about 600 nsin length, or about 540 ns in length). In some embodiments, the pulsesare about 100 ns or more in length (such as about 150 ns or more, 200 nsor more, 300 ns or more, 400 ns or more, 500 ns or more, 540 ns or more,600 ns or more, 700 ns or more, 800 ns or more, 900 ns or more, 1000 nsor more, 1200 ns or more, or 1500 ns or more in length). In someembodiments, the pulses are about 2000 ns or less in length (such asabout 1500 ns or less, 1200 ns or less, 1000 ns or less, 900 ns or less,800 ns or less, 700 ns or less, 600 ns or less, 500 ns or less, 400 nsor less, 300 ns or less, 200 ns or less, or 150 ns or less in length).In some embodiments, the pulses are separated by a dwell time. In someembodiments, the dwell time is about 100 ns or more in length (such asabout 150 ns or more, 200 ns or more, 300 ns or more, 400 ns or more,500 ns or more, 540 ns or more, 600 ns or more, 700 ns or more, 800 nsor more, 900 ns or more, 1000 ns or more, 1200 ns or more, or 1500 ns ormore in length). In some embodiments, the dwell time is about 2000 ns orless in length (such as about 1500 ns or less, 1200 ns or less, 1000 nsor less, 900 ns or less, 800 ns or less, 700 ns or less, 600 ns or less,500 ns or less, 400 ns or less, 300 ns or less, 200 ns or less, or 150ns or less in length). In some embodiments, the pulses are square,rectangular, triangular, sawtooth, or sinusoidal. In some embodiments,the pulse output can be two-level (GND and POS), three-level (GND, NEG,POS), 5-level, or any other multiple-level (for example, if using 24-bitDAC). In some embodiments, the pulses are continuously transmitted bythe interrogator during operation. In some embodiments, when the pulsesare continuously transmitted by the interrogator a portion of thetransducers on the interrogator are configured to receive ultrasonicwaves and a portion of the transducers on the interrogator areconfigured to transmit ultrasonic waves. Transducers configured toreceive ultrasonic waves and transducers configured to transmitultrasonic waves can be on the same transducer array or on differenttransducer arrays of the interrogator. In some embodiments, a transduceron the interrogator can be configured to alternatively transmit orreceive the ultrasonic waves. For example, a transducer can cyclebetween transmitting one or more pulses and a pause period. Thetransducer is configured to transmit the ultrasonic waves whentransmitting the one or more pulses, and can then switch to a receivingmode during the pause period. In some embodiments, the one or morepulses in the cycle includes about 1 to about 10 pulses (such as about 2to about 8, or about 4 to about 7, or about 6) pulses of ultrasonicwaves in any given cycle. In some embodiments, the one or more pulses inthe cycle includes about 1 or more, 2 or more, 4 or more, 6 or more, 8or more, or 10 or more pulses of ultrasonic waves in any given cycle. Insome embodiments, the one or more pulses in the cycle includes about 20or fewer, about 15 or fewer, about 10 or fewer, about 8 or fewer, orabout 6 or fewer pulses in the cycle. The pulse cycle can be regularlyrepeated, for example every about 50 microseconds (μs) to about 300 μs(such as about every 75 μs to about 200 μs, or every about 100 μs)during operation. In some embodiments, the cycle is reaped every 50 μsor longer, every 100 μs or longer, every 150 μs or longer, every 200 μsor longer, every 250 μs or longer, or every 300 μs or longer. In someembodiments, the cycle is repeated every 300 μs or sooner, every 250 μsor sooner, every 200 μs or sooner, every 150 μs or sooner, or every 100μs or sooner. The cycle frequency can set, for example, based on thedistance between the interrogator and the implantable device and/or thespeed at which the transducer can toggle between the transmitting andreceiving modes.

FIG. 5 illustrates cycled pulse-echo ultrasonic communication betweenthe interrogator and the implantable device. FIG. 5A shows a series ofpulse cycles with a frequency of every 100 microseconds. During thetransmission of the pulses, the transducers in the array are configuredto transmit the ultrasonic waves. After the pulses are transmitted, thetransducers are configured to receive backscattered ultrasonic waves.FIG. 5B shows a zoom-in view of a cycle, which shows six pulses ofultrasonic waves, with a frequency of every 540 nanoseconds.Backscattered ultrasonic waves detected by the interrogator are shown inFIG. 5C, with a zoom-in view of a single pulse shown in FIG. 5D. Asshown in FIG. 5D, the ultrasonic backscatter received from theimplantable device can be analyzed, which may include filtering (forexample, to remove the wave decay) the backscattered waves, rectifyingthe backscattered waves, and integrating the waves to determine the dataencoded by the waves. In some embodiments, the backscatter waves areanalyzed using a machine learning algorithm. FIG. 5E shows a zoomed inversion of the filtered backscattered waves. The backscatter wave shownin FIG. 5E includes four distinct regions corresponding to reflectionsarising from mechanical boundaries: (1) reflection from thebiocompatible material that encapsulates the implantable device; (2)reflection from the top surface of the miniaturized ultrasonictransducer; (3) reflection from the boundary between the printed circuitboard and the miniaturized ultrasonic transducer; and (4) reflectionfrom the back of the printed circuit board. The amplitude of thebackscatter waves reflected from the surface of the miniaturizedtransducer changed as a function of changes in impedance of the currentreturning to the miniaturized ultrasonic transducer, and can be referredto as the “responsive backscatter” since this region of the backscatterencodes information relating to the sensed physiological condition. Theother regions of the ultrasonic backscatter can be referred to as“non-responsive backscatter,” and are useful in determining the positionof the implantable device, movement of the implantable device, and/ortemperature changes proximal to the implantable device, as explainedbelow. In some embodiments, the device further comprises anon-responsive reflector. In some embodiments, the non-responsivereflector is a cube. In some embodiments, the non-responsive reflectorcomprises silicon. In some embodiments, the non-responsive reflector isa surface of rigid material. The non-responsive reflector is attached tothe implantable device but electrically isolated, and can reflectultrasonic waves that are not responsive to changes in sensor or ASICimpedance, for example due to a sensed physiological condition by thesensor.

The frequency of the ultrasonic waves transmitted by the transducer canbe set depending on the drive frequency or resonant frequency of theminiaturized ultrasonic transducer on the implantable device. In someembodiments, the miniaturized ultrasonic transducers are broad-banddevices. In some embodiments, the miniaturized ultrasonic transducersare narrow-band. For example, in some embodiments the frequency of thepulses is within about 20% or less, within about 15% or less, withinabout 10% or less, within about 5% or less of the resonant frequency ofthe miniaturized ultrasonic transducer. In some embodiments, the pulsesare set to a frequency about the resonant frequency of the miniaturizedultrasonic transducer. In some embodiments, the frequency of theultrasonic waves is between about 100 kHz and about 100 MHz (such asbetween about 100 kHz and about 200 kHz, between about 200 kHz and about500 kHz, between about 500 kHz and about 1 MHz, between about 1 MHz andabout 5 MHz, between about 5 MHz and about 10 MHz, between about 10 MHzand about 25 MHz, between about 25 MHz and about 50 MHz, or betweenabout 50 MHz and about 100 MHz). In some embodiments, the frequency ofthe ultrasonic waves is about 100 kHz or higher, about 200 kHz orhigher, about 500 kHz or higher, about 1 MHz or higher, about 5 MHz orhigher, about 10 MHz or higher, about 25 MHz or higher, or about 50 MHzor higher. In some embodiments, the frequency of the ultrasonic waves isabout 100 MHz or lower, about 50 MHz or lower, about 25 MHz or lower,about 10 MHz or lower, about 5 MHz or lower, about 1 MHz or lower, about500 kHz or lower, or about 200 kHz or lower. Higher frequency allows fora smaller miniaturized ultrasonic transducer on the implantable device.However, higher frequency also limits the depth of communication betweenthe ultrasonic transducer and the implantable device. In someembodiments, the implantable device and the ultrasonic transducer areseparated by about 0.1 cm to about 15 cm (such as about 0.5 cm to about10 cm, or about 1 cm to about 5 cm). In some embodiments, theimplantable device and the ultrasonic transducer are separated by about0.1 cm or more, about 0.2 cm or more, about 0.5 cm or more, about 1 cmor more, about 2.5 cm or more, about 5 cm or more, about 10 cm or more,or about 15 cm or more. In some embodiments, the implantable device andthe ultrasonic transducer are separated by about 20 cm or less, about 15cm or less, about 10 cm or less, about 5 cm or less, about 2.5 cm orless, about 1 cm or less, or about 0.5 cm or less.

In some embodiments, the backscattered ultrasound is digitized by theimplantable device. For example, the implantable device can include anoscilloscope or analog-to-digital converter (ADC) and/or a memory, whichcan digitally encode information in current (or impedance) fluctuations.The digitized current fluctuations, which reflect data sensed by thesensor, are received by the ultrasonic transducer, which then transmitsdigitized acoustic waves. The digitized data can compress the analogdata, for example by using singular value decomposition (SVD) and leastsquares-based compression. In some embodiments, the compression isperformed by a correlator or pattern detection algorithm. Thebackscatter signal may go through a series of non-linear transformation,such as 4^(th) order Butterworth bandpass filter rectificationintegration of backscatter regions to generate a reconstruction datapoint at a single time instance. Such transformations can be done eitherin hardware (i.e., hard-coded) or in software.

In some embodiments, an interrogator communicates with a plurality ofimplantable devices. This can be performed, for example, usingmultiple-input, multiple output (MIMO) system theory. For example,communication between the interrogator and the plurality of implantabledevices using time division multiplexing, spatial multiplexing, orfrequency multiplexing. In some embodiments, two or more (such as 3, 4,5, 6, 7, 8, 9, 10 or more, 12 or more, about 15 or more, about 20 ormore, about 25 or more, about 50 or more, or about 100 or more)implantable devices communicate with the interrogator. In someembodiments, about 200 or fewer implantable devices (such as about 150or fewer, about 100 or fewer, about 50 or fewer, about 25 or fewer,about 20 or fewer, about 15 or fewer, about 12 or fewer, or about 10 orfewer implantable devices) are in communication with the interrogator.The interrogator can receive a combined backscatter from the pluralityof the implantable devices, which can be deconvoluted, therebyextracting information from each implantable device. In someembodiments, interrogator focuses the ultrasonic waves transmitted froma transducer array to a particular implantable device through beamsteering. The interrogator focuses the transmitted ultrasonic waves to afirst implantable device, receives backscatter from the firstimplantable device, focuses transmitted ultrasonic waves to a secondimplantable device, and receives backscatter from the second implantabledevice. In some embodiments, the interrogator transmits ultrasonic wavesto a plurality of implantable devices, and then receives ultrasonicwaves from the plurality of implantable devices.

In some embodiments, the interrogator is used to determine the locationor velocity of the implantable device. Velocity can be determined, forexample, by determining the position or movement of a device over aperiod of time. The location of the implantable device can be a relativelocation, such as the location relative to the transducers on theinterrogator. A plurality of transducers, which may be disposed on thesame transducer array or two or more different transducer arrays, cancollect backscatter ultrasonic waves from an implantable device. Basedon the differences between the backscatter waveform arising from thesame implantable device and the known location of each transducer, theposition of the implantable device can be determined. This can be done,for example by triangulation, or by clustering and maximum likelihood.The differences in the backscatter may be based on responsivebackscatter waves, non-responsive backscatter waves, or a combinationthereof.

In some embodiments, the interrogator is used to track movement of theimplantable device. Movement of the implantable device that can betracked by the interrogator includes lateral and angular movement. Suchmovement may arise, for example, due to shifting of one or more organssuch as the liver, stomach, small or large intestine, kidney, pancreas,gallbladder, bladder, ovaries, uterus, or spleen (which may be theresult, for example, of respiration or movement of the subject) orvariations in blood flow (such as due to a pulse). Thus, in someembodiments, the implantable device is useful for tracking movement ofan organ or a pulse rate. Movement of the implantable device can betracked, for example, by monitoring changes in the non-responsivebackscatter waves. In some embodiments, movement of the implantabledevice is determined my comparing the relative location of theimplantable device at a first time point to the relative location of theimplantable device at a second time point. For example, as describedabove, the location of an implantable device can be determined using aplurality of transducers on the interrogated (which may be on a singlearray or on two or more arrays). A first location of the implantabledevice can be determined at a first time point, and a second location ofthe implantable device can be determined at a second time point, and amovement vector can be determined based on the first location at thefirst time point and the second location at the second time point.

Implantable Device

The implantable device includes a miniaturized ultrasonic transducer(such as a miniaturized piezoelectric transducer, a capacitivemicro-machined ultrasonic transducer (CMUT), or a piezoelectricmicro-machined ultrasonic transducer (PMUT)) and a physiological sensor(such as a temperature sensor, an oxygen sensor, a pH sensor, a strainsensor, a pressure sensor, or a glucose sensor). In some embodiments, anapplication specific integrated circuit (ASIC) is included in theimplantable device, which can communicate between the physiologicalsensor and the miniaturized ultrasonic transducer. The interrogatortransmits ultrasonic waves, which can power and communicate with theimplantable device through the miniaturized ultrasonic transducer on theimplantable device. The changed impedance impacts the current flowingwithin the miniaturized ultrasonic transducer, which impacts theultrasonic backscatter. Thus, a change in the physiological conditionimpacts the ultrasonic backscatter, which can be detected by theinterrogator. FIG. 6A illustrates a schematic of the implantable devicewith a miniaturized ultrasonic transducer 602 and a physiological sensor604. FIG. 6B illustrates a schematic of the implantable device with aminiaturized ultrasonic transducer 606, an ASIC 608, and a physiologicalsensor 610.

The implantable devices are miniaturized, which allows for comfortableand long-term implantation while limiting tissue inflammation that isoften associated with implantable devices. In some embodiments, thelongest dimension of the device is about 5 mm or less, about 4 mm orless, about 3 mm or less, about 2 mm or less, about 1 mm or less, about0.5 mm or less, about 0.3 mm or less, about 0.1 mm or less in length. Insome embodiments, the longest dimension of the device is about 0.05 mmor longer, about 0.1 mm or longer, about 0.3 mm or longer, about 0.5 mmor longer, about 1 mm or longer, about 2 mm or longer, or about 3 mm orlonger in the longest dimension of the device. In some embodiments, thelongest dimension of the device is about 0.04 mm to about 5 mm inlength, about 0.05 mm to about 4 mm in length, about 0.07 mm to about 3mm in length, about 0.08 mm to about 3 mm in length, or about 1 mm toabout 2 mm in length.

In some embodiments, the implantable device has a volume of about 5 mm³or less (such as about 4 mm³ or less, 3 mm³ or less, 2 mm³ or less, or 1mm³ or less). In certain embodiments, the implantable device has avolume of about 0.5 mm³ to about 5 mm³, about 1 mm³ to about 5 mm³,about 2 mm³ to about 5 mm³, about 3 mm³ to about 5 mm³, or about 4 mm³to about 5 mm³. The small size of the implantable device allows forimplantation of the device using a biopsy needle.

In some embodiments, the implantable device is implanted in a subject.The subject can be for example, an animal, such as a mammal. In someembodiments, the subject is a human, dog, cat, horse, cow, pig, sheep,goat, chicken, monkey, rat, or mouse. In some embodiments, the subjectis a plant. Implantable devices implanted in plants can be useful, forexample, for monitoring conditions of agricultural plants.

In some embodiments, the implantable device or a portion of theimplantable device (such as the miniaturized ultrasonic transducer, theASIC, or all or a portion of the sensor) is encapsulated by abiocompatible material (such as a biocompatible polymer), for example acopolymer of N-vinyl-2-pyrrolidinone (NVP) and n-butylmethacrylate(BMA), polydimethylsiloxane (PDMS), parylene, polyimide, siliconnitride, silicon dioxide, alumina, niobium, hydroxyapatite, or siliconcarbide. The silicon carbide can be amorphous silicon carbide orcrystalline silicon carbide. The biocompatible material is preferablyimpermeable to water to avoid damage or interference to electroniccircuitry within the device. In some embodiments, the implantable deviceor portion of the implantable device is encapsulated by a ceramic (forexample, alumina or titania) or a metal (for example, steel ortitanium).

In some embodiments, the miniaturized ultrasonic transducer and, ifpresent, the ASIC, are disposed on a printed circuit board (PCB). Thesensor can optionally be disposed on the PCB, or can otherwise beconnected to the ASIC. FIGS. 7A and 7B illustrate exemplaryconfigurations of the implantable device including a PCB. FIG. 7A showsthe piezoelectric transducer 702 and an ASIC 704 disposed on a firstside 706 of the PCB 708. A first electrode 710 and a second electrode712 are disposed on a second side 714 of the PCB 708. The firstelectrode 710 and the second electrode 712 can be, for example,components of the sensor. FIG. 7B sows the piezoelectric transducer 714on a first side 716 of the PCB 718, and the ASIC 720 on the second side722 of the PCB 718. A first electrode 724 is disposed on the first side716 of the PCB, and a second electrode 726 is disposed on the secondside 722 of the PCB 718. The first electrode 724 and the secondelectrode 726 can be, for example, components of the sensor.

The miniaturized ultrasonic transducer of the implantable device can bea micro-machined ultrasonic transducer, such as a capacitivemicro-machined ultrasonic transducer (CMUT) or a piezoelectricmicro-machined ultrasonic transducer (PMUT), or can be a bulkpiezoelectric transducer. Bulk piezoelectric transducers can be anynatural or synthetic material, such as a crystal, ceramic, or polymer.Exemplary bulk piezoelectric transducer materials include bariumtitanate (BaTiO₃), lead zirconate titanate (PZT), zinc oxide (ZO),aluminum nitride (AlN), quartz, berlinite (AlPO₄), topaz, langasite(La₃Ga₅SiO₁₄), gallium orthophosphate (GaPO₄), lithium niobate (LiNbO₃),lithium tantalite (LiTaO₃), potassium niobate (KNbO₃), sodium tungstate(Na₂WO₃), bismuth ferrite (BiFeO₃), polyvinylidene (di)fluoride (PVDF),and lead magnesium niobate-lead titanate (PMN-PT).

In some embodiments, the miniaturized bulk piezoelectric transducer isapproximately cubic (i.e., an aspect ratio of about 1:1:1(length:width:height). In some embodiments, the piezoelectric transduceris plate-like, with an aspect ratio of about 5:5:1 or greater in eitherthe length or width aspect, such as about 7:5:1 or greater, or about10:10:1 or greater. In some embodiments, the miniaturized bulkpiezoelectric transducer is long and narrow, with an aspect ratio ofabout 3:1:1 or greater, and where the longest dimension is aligned tothe direction of propagation of the carrier ultrasound wave. In someembodiments, one dimension of the bulk piezoelectric transducer is equalto one half of the wavelength (λ) corresponding to the drive frequencyor resonant frequency of the transducer. At the resonant frequency, theultrasound wave impinging on either the face of the transducer willundergo a 180° phase shift to reach the opposite phase, causing thelargest displacement between the two faces. In some embodiments, theheight of the piezoelectric transducer is about 10 μm to about 1000 μm(such as about 40 μm to about 400 μm, about 100 μm to about 250 μm,about 250 μm to about 500 μm, or about 500 μm to about 1000 μm). In someembodiments, the height of the piezoelectric transducer is about 5 mm orless (such as about 4 mm or less, about 3 mm or less, about 2 mm orless, about 1 mm or less, about 500 μm or less, about 400 μm or less,250 μm or less, about 100 μm or less, or about 40 μm or less). In someembodiments, the height of the piezoelectric transducer is about 20 μmor more (such as about 40 μm or more, about 100 μm or more, about 250 μmor more, about 400 μm or more, about 500 μm or more, about 1 mm or more,about 2 mm or more, about 3 mm or more, or about 4 mm or more) inlength.

In some embodiments, the ultrasonic transducer has a length of about 5mm or less such as about 4 mm or less, about 3 mm or less, about 2 mm orless, about 1 mm or less, about 500 μm or less, about 400 μm or less,250 μm or less, about 100 μm or less, or about 40 μm or less) in thelongest dimension. In some embodiments, the ultrasonic transducer has alength of about 20 μm or more (such as about 40 μm or more, about 100 μmor more, about 250 μm or more, about 400 μm or more, about 500 μm ormore, about 1 mm or more, about 2 mm or more, about 3 mm or more, orabout 4 mm or more) in the longest dimension.

The miniaturized ultrasonic transducer is connected two electrodes; thefirst electrode is attached to a first face of the transducer and thesecond electrode is attached to a second face of the transducer, whereinthe first face and the second face are opposite sides of the transduceralong one dimension. In some embodiments, the electrodes comprisesilver, gold, platinum, platinum-black, poly(3,4-ethylenedioxythiophene(PEDOT), a conductive polymer (such as conductive PDMS or polyimide), ornickel. In some embodiments, the transducer is operated in shear-modewhere the axis between the metallized faces (i.e., electrodes) of thetransducer is orthogonal to the motion of the transducer.

The miniaturized ultrasonic transducer is connected to a sensor and, insome embodiments, an AISC. The ASIC, if present, can be integrated withthe sensor or provide separately from the sensor.

The ASIC used in the implantable device depends, in part, on the sensorthat is attached. In some embodiments, the AISC is fully integrated withthe sensor, and in some embodiments the sensor is provided as aseparate, but attached, component of the implantable device. In someembodiments, the implantable device includes two or more sensors, andone or more ASICs can be used with the two or more sensors. For example,in some embodiments, a single ASIC is used with two or more, three ormore, four or more, or five or more sensors.

In some embodiments, the ASIC includes a power circuit, which isconfigured to power components of the implanted device. The powercircuit can include, for example, a rectifier, a charge pump, and/or anenergy storage capacitor. In some embodiments, the energy storagecapacitor is included as a separate component. Ultrasonic waves thatinduce a voltage differential in the miniaturized ultrasonic transducerprovide power for the implantable device, which can be managed by thepower circuit.

In some embodiments, the ASIC comprises one or more analog circuit whichutilizes the electrical power provided by the transducer to power one ormore analog amplifiers, increasing the modulation depth of the signalmodulated onto the backscatter impedance. In some embodiments the ASICincludes one or more digital circuits, which can include a memory andone or more circuit blocks or systems for operating the implantabledevice; these systems can include, for example an onboardmicrocontroller, a finite state machine implementation or digitalcircuits capable of executing programs stored on the implant or providedvia ultrasonic communication between interrogator and implant. In someembodiments, the digital circuit includes an analog-to-digital converter(ADC), which can convert analog signal from the sensor into a digitalsignal. In some embodiments, the digital circuit includes adigital-to-analog converter (DAC), which converts a digital signal intoan analog signal prior to directing the signal to a modulator.

The digital circuit can operate a modulation circuit (which can also bereferred to as the “backscatter circuit”), which connects to theminiaturized ultrasonic transducer. The modulation circuit includes aswitch, such as an on/off switch or a field-effect transistor (FET). Anexemplary FET that can be used with some embodiments of the implantabledevice is a metal-oxide-semiconductor field-effect transistor (MOSFET).The modulation circuit can alter the impedance presented to theminiaturized ultrasonic transducer, and the variation in current passingthrough the transducer encodes signals transmitted by the digitalcircuit. The digital circuit can also operate one or more amplifiers,which amplifies the current directed to the switch. In embodiments wherethe digital circuit is omitted, the impedance in the modulation circuitcan be directly controlled by the sensor.

In some embodiments, the ASIC includes a driver circuit, which providescurrent to one or more sensors. The driver circuit can be operated bythe digital circuit if present. In some embodiments, one or moreamplifiers are disposed between the driver circuit and the digitalcircuit. In some embodiments, the ASIC includes a front end circuit(such as a CMOS front end), which can receive a signal from the sensor.The signal received by the front end circuit can be relayed to thedigital circuit.

FIG. 8A includes one embodiment of a miniaturized ultrasonic transducer(identified as the “piezo”) connected to an ASIC. The ASIC includes apower circuit, a modulation circuit (or “backscatter circuit”), and adriver (the “stimulation circuit”). The power circuit includes an energystorage capacitor (“cap”).

FIG. 8B illustrates another example of an ASIC 802 connected to theminiaturized ultrasonic transducer 804. In the illustrated embodiment,the miniaturized ultrasonic transducer 804 is connected to a powercircuit 806. The power circuit 806 provides power to the othercomponents of the ASIC, including the modulation circuit 808, thedigital circuit 810, the driver 812, and the front end 814. The digitalcircuit 810 operates the driver 812, which can be connected to a sensor(not shown). The front end circuit 814 receives signal from the sensorand transmits the signal to the digital circuit 810. The digital circuit810 can then control the modulation circuit 808, which controlsimpedance of the current returning to the miniaturized ultrasonictransducer 804.

Sensors

The implantable device includes one or more sensors. The sensors areconfigured to detect a physiological condition, such as temperature,oxygen concentration, pH, an analyte (such as glucose), strain, orpressure. Variation in the physiological condition modulates impedance,which in turn modulates current flowing miniaturized ultrasonictransducer on the implantable device. As explained above, this producesultrasonic backscatter detected by the interrogator; changes in theultrasonic backscatter waves reflect information about the physiologicalcondition. In some embodiments, the system is configured to detectchanges in the physiological system. In some embodiments, the system isconfigured detect a value or an approximate value of the physiologicalcondition, for example by calibrating the ultrasonic backscatter toknown values.

The implantable device may comprise one or more (such as 2, 3, 4, 5 ormore) sensors, which may detect the same physiological condition ordifferent physiological conditions. In some embodiments, the implantabledevice comprises 10, 9, 8, 7, 6 or 5 or fewer sensors). For example, insome embodiments, the implantable device comprises a first sensorconfigured to detect temperature and a second sensor configured todetect oxygen. Changes in both physiological conditions can be encodedin the ultrasonic backscatter waves, which can be deciphered by anexternal computing system.

In some embodiments, the sensor includes an optical detector. A lightsource (such as a light emitting diode or vertical cavity surfaceemitting laser (VCSEL)) emits a light, which is detected by the opticaldetector. The amount of light detected by the optical detector isindicative of the physiological condition detected. A front end (such asa CMOS front end) can receive a signal from the detector, which canalter the impedance presented to the ultrasonic transducer. In someembodiments, a digital circuit receives the signal from the front endcircuit and operates a modulation circuit, which modulates the impedancepresented to the ultrasonic transducer. The ultrasonic backscattertransmitted from the miniaturized ultrasonic transducer to theinterrogator thus encodes information from the detected physiologicalcondition.

The light source can be disposed outside of the tissue, implanted withinthe tissue, or as part of the implantable device itself (which may becontrolled by a driver on the ASIC). In some embodiments, the lightsource emits light in the near infrared range (e.g., a wavelength ofabout 780 nm to about 2500 nm). In some embodiments, a plurality oflight sources are include, which may emit light at differentwavelengths. In some embodiments the implantable device is used fornear-infrared spectroscopy, which can be used to detect certain analytesin blood or interstitial tissue, such as glucose. In some embodiments,the light source emits light outside of the infrared range (such as at awavelength below about 780 nm or above about 2500 nm). Since there is adistance limit when transmitting light through tissue (generally lessthan about 2 cm), it is generally preferable to include the light sourceon the implantable device when using the implantable device at depthsgreater than about 2 cm. In some embodiments, the implantable device isimplanted at a depth of about 2 cm or more (such as about 3 cm or more,about 4 cm or more, or about 5 cm or more).

FIG. 9A illustrates an implantable device 902 implanted in tissuedetecting light and emitting ultrasonic backscatter waves. Theimplantable device 902 further receives ultrasonic waves from anexternal ultrasonic transducer (not shown). The implantable devicereceives light from an external light source 904. Changes in the amountof light detected by the implantable device due to changes in aphysiological condition modulate the ultrasonic backscatter. FIG. 9Aillustrates a system comprising an implantable device comprising anoptical detector implanted in tissue in optical communication with anexternal light source. In the simplest form, the implantable device canbe embedded in the tissue with an external optical emitter (visiblelight, NIR, near ultraviolet or otherwise) for optical sensing. Theexternal optical emitter can be coupled with an external transceiver, ormay be a separate component. The embodiment illustrated in FIG. 9Ademonstrates the utilization of an optical filter to ensure detection ofthe intensity of only a single wavelength or multiple selectedwavelengths. This optical emitter may be a monochromatic light source ora broadband light source. Furthermore, the optical emitter can beimplanted in the body. The emitter may be on-board or independentlyimplanted. Power transmission, local temperature elevation and implantsize would have to be considered when implanting the optical emitter inthe patient.

In some embodiments, the light source emits broadband light. In someembodiments, the light source emits narrowband light. For example, thelight source can include an optical filter, and can emit narrowbandlight at one or more predetermined wavelengths. In some embodiments, thelight source emits narrowband light at one or more, two or more, threeor more, or four of more different wavelengths. In some embodiments, thelight source emits narrowband light a plurality of differentwavelengths, wherein at least one narrowband light wavelength is usedfor error correction. It has been demonstrated that by alternatelypulsing monochromatic light of three wavelengths in the NIR spectralregion and utilizing NIR light of a fourth wavelength for error correct,tissue oxygenation levels can be monitored due to the absorptivebehavior of hemoglobin, myoglobin, and cytochrome aa3. This is shown inFIG. 9B. In FIG. 9B, an implantable device 906 is implanted in tissueand receives narrow band light from four different light sources (lightsource 908, light source 910, light source 912, and light source 914),wherein each light source emits a different narrowband light wavelength.As illustrated, light source 908, light source 910, light source 912,and light source 914 are positioned external to the tissue. Theimplantable device 906 further receives ultrasonic waves from anexternal ultrasonic transducer (not shown). Changes in the amount oflight detected by the implantable device due to changes in aphysiological condition modulate the ultrasonic backscatter.

Analyte measurements may also be conducted through means other than NIRspectroscopy. One such example is through the use of optodes forchemical sensing. Scattering should be considered and taken into accountwhen using light outside of the NIR spectral region.

FIG. 9C illustrates an implantable device 916 comprising the lightsource 918. The implantable device further includes a light detector(not shown), which can receive light from the light source 918. Theimplantable device 906 further receives ultrasonic waves from anexternal ultrasonic transducer (not shown), which can power theimplantable device 916, including the light source 918. Changes in theamount of light detected by the implantable device due to changes in aphysiological condition modulate the ultrasonic backscatter.

Implantable devices with optical sensors can be useful for a variety ofpurposes. For example, the implantable device can be used to monitoroxygen levels (including blood oxygen levels or interstitial fluidoxygen levels) in a subject, tumor oxygenation monitoring, functionalbrain imaging, blood analyte measurements, tissue engineering (such asto monitor for anoxia and hypoxia), and pH measurements. In someembodiments, the optical sensor is used for determining a blood pressureor a pulse rate.

In some embodiments, the sensor on the implantable device is an oxygensensor or a pH sensor. An implantable device comprising an oxygen sensoror pH sensor can be useful for monitoring physiological oxygenconcentration (such as blood oxygen or interstitial fluid oxygen) orphysiological pH (such blood pH or interstitial fluid pH). The oxygenconcentration or pH can be localized to the vicinity of the implantabledevice, or, if a network of devices is used, the measured oxygenconcentration or pH can by a systemic physiological measurement. Thiscan be useful, for example, in monitoring hypoxia or acidemia. Theimplantable device can include a miniaturized ultrasonic transducer(such as a bulk piezoelectric transducer, a PMUT, or a CMUT), an ASIC(which may include a driver and a front end), and an oxygen or pHsensor.

In some embodiments, an oxygen sensor comprises a Clark electrode. AClark electrode measures oxygen on a catalytic surface (such as aplatinum surface) surrounded by a membrane, and can be miniaturized tobe included on an implantable device. The Clark electrode can beattached to the ASIC on the implantable device, and variance in theamount of oxygen sensed by the implantable device (which may be bloodoxygen or interstitial fluid oxygen) can modulate the ultrasonicbackscatter.

In some embodiments, the oxygen sensor includes a light source (such asa light emitting diode or vertical cavity surface emitting laser(VCSEL)) and an optical detector (such as a phototransistor or aphotovoltaic cell, or an array of phototransistors or photovoltaiccells). A matrix including an oxygen-sensitive fluorophore or apH-sensitive fluorophore is disposed over the light source and the lightdetector, or in a position bridging the light source and the lightdetector, and the amount of light detected by the light source dependson the amount of oxygen in or the pH of the surrounding fluid. Suchdevices can be referred to as optrodes. The matrix can include, forexample, an oxygen-sensitive fluorophore (such as a rutheniumfluorophore) or pH-sensitive fluorophore in a polymer, and increasedoxygen or increased or decreased pH (depending on the choice offluorophore) can cause a faster decay of fluorescence and a decrease inintensity. This oxygen- or pH-dependent change in intensity andfluorescence decay lifetime can be detected by the optical detector. Insome embodiments, the matrix is a hydrogel or polydimethylsiloxane(PDMS) polymer containing a ruthenium fluorophore. In some embodimentsthe ruthenium fluorophore is bound to silica particles or silicasurfaces contained within the matrix (these can be made by sol-gelprocesses, for example). The matrix protects the fluorophore fromcomponents in the extracellular fluid and inhibits adhesion of proteins,cells and other cellular debris that could affect the diffusion ofoxygen into the matrix. Further, encapsulation of the ruthenium metal inthe matrix reduces potential toxicity of the ruthenium. The light sourceand/or optical detector can optionally include a filter to limit emittedor detected light to a narrow bandwidth. The ASIC can drive the lightsource to emit a pulsed or sinusoidal light signal, which causes thelight source to emit the light. The light emitted by the light sourcecauses the fluorophore in the matrix to fluoresce. For example, in someembodiments the light source emits a blue light or a UV light, and thefluorophore can emit an orange or red light. The fluorescence intensityand/or lifetime (decay) of fluorescence is a function of the oxygenconcentration or pH of the matrix, which is influenced by thesurrounding fluid (e.g., blood or interstitial fluid). From thefluorescence decay, a fluorescent lifetime decay constant can bedetermined, which can reflects the oxygen amount or pH.

Use of a light pulse emitted from the light source allows for theobservation of fluoresce decay or fluorescence lifetime, which isdependent on pH or oxygen concentration. This is shown in FIG. 10A.Thus, in some embodiments, the decay of fluorescence (the fluorescencelifetime) following a light pulse from the light source is used tomeasure the oxygen concentration or the pH surrounding the sensor.

Use of an oscillating light source allows for the fluorescence emissionto be offset from the light source due to the decay of fluorescence(fluorescence lifetime). The phase shift between the light source waveand the fluorescence detection is dependent on the concentration ofoxygen or pH. This is shown in FIG. 10B. The phase shift co can bedetermined as follows:

tan φ=(27πf)×τ

wherein f is the oscillation frequency of the light emitted from thelight source, and r is the lifetime of the fluorescence decay (whichdepends on the oxygen or pH concentration). Thus, in some embodiments anoscillating light source is used, and the phase shift of the lightsource relative to the fluorescence is used to determine pH or oxygenconcentration surrounding the sensor. An exemplary optical detector thatcan be used to measure a phase shift is shown in FIG. 10C. The lightsource 1002 includes an oscillator 1004, and emits light toward a matrix1006. The matrix 1006 includes an oxygen-sensitive or pH-sensitivefluorophore, which is detected by the optical detector 1008. The opticaldetector 1008 includes a photodiode (or a photodiode array) 1010, whichtransmits current to a current to voltage conversion module (such as atransimpedance amplifier (TIA) or voltage buffer) 1012. The opticaldetector 1008 may further include an amplifier 1014. A phase detector1016 is included, which can determine the phase difference between theoscillating light emitted by the light source 1002 and the lightdetected by the optical detector 1008. An optional optical filter (suchas a long pass filter) 1018 can be included between the matrix 1006 andthe optical detector 1008. In some embodiments, a light sourced can bepulsed and the fluorescence lifetime can be measured by sampling thefluorescence upon extinguishing the light source (i.e. from the fallingedge of the pulse).

The optical detector detects the light emitted by the fluorophore, whichis read by the ASIC. In some embodiments, the ASIC modulates current tothe miniaturized ultrasonic transducer as a function of the raw signal(or some portion of the raw signal) from the optical detector, and theminiaturized ultrasonic transducer can emit backscatter ultrasonic wavesreflecting the detected signal. In some embodiments, the ASIC modulatesthe impedance presented to the transducers as a digital representationof the raw or compressed signal. In some embodiments, the ASIC itselfcalculates the oxygen concentration or pH, and sends a signal to theminiaturized ultrasonic transducer encoding the signal. In someembodiments, the external ultrasonic transceiver pulses ultrasonicwaves, which causes pulses of current through the implantable device(and, in turn, pulses of light). Between the pulses of current, theminiaturized ultrasonic transducer emits the ultrasonic backscatterecho.

FIG. 11A illustrates one embodiment of an implantable device with anoxygen sensor or pH sensor. The implantable device includes aminiaturized ultrasonic transducer 1102, an ASIC 1104, and a pH oroxygen sensor 1106. The sensor 1106 includes a light source (such as alight emitting diode) 1108, a pH-sensitive or oxygen-sensitive matrix1110, and an optical detector 1112 (such as a photovoltaic, aphototransistor, or any other suitable optical detector known in theart). The matrix 1110 includes an oxygen sensitive fluorophore (for anoxygen sensor) or a pH sensitive fluorophore (for a pH sensor).Optionally, a filter 1114 is disposed between the light source 1108 andthe matrix 1110. The filter can be configured to allow a narrowbandlight to be transmitted to the matrix 1110. In some embodiments, inaddition to or in place of filter 1114, a filter 1116 is disposedbetween the matrix 1110 and the optical detector 1112. The filter 1116can be configured to allow a narrowband light to enter the opticaldetector 1112. The light source 1108 is powered by a driver 1118, andthe optical detector 1112 transmits a signal received by a front end(such as a CMOS front end) 1120. The front end 1120 and the driver 1118are connected to a digital circuit 1122, which controls a modulationcircuit 1124 (the digital circuit can include appropriate conversioncircuitry to properly measure and sample the detector signal) Themodulation circuit controls the impedance presented to the miniaturizedultrasonic transducer 1102, which emits backscatter waves to aninterrogator. The ASIC 1104 can also include a power circuit 1126, whichprovides power to components of the ASIC; the power circuit derivespower from the transducer. In the embodiment shown in FIG. 11A, thelight source 1108 and the optical detector 1112 are directed in the samedirection. FIG. 11B illustrates an alternative configuration of theimplantable device with an oxygen sensor or a pH sensor, with the lightsource 1108 and the optical detector 1112 are directed toward eachother.

In some embodiments, the optical sensor is used to determine bloodpressure or a pulse rate. For example, the optical sensor can include amembrane. Light from the light source is focused on the membrane, andthe membrane reflects the light, which is detected by the opticaldetector. The membrane is deformed by pressure, and the deformations arecause variation in the reflected light.

In some embodiments, an implantable device with a temperature sensorincludes a miniaturized ultrasonic transducer (such as a bulkpiezoelectric transducer, a PMUT, or a CMUT) and a temperature sensor(such as a proportional to absolute temperature (PTAT) circuit, athermocouple, or a thermistor). In some embodiments, the thermistor is anegative temperature coefficient (NTC) thermistor. In some embodiments,the thermistor is a positive temperature coefficient (NTC) thermistor.In some embodiments, the implantable device further comprises an ASIC(which optionally includes a front end, such as a CMOS front end, or adriver), which may be integrated with or distinguishable from thetemperature sensor. In some embodiments, the ASIC includes a digitalcircuit, a modulation circuit, or a power circuit; the power circuitderives power from the transducer. In some embodiments, the implantabledevice does not include an ASIC. The impedance presented to thetransducer by the temperature sensor depends on the measuredtemperature, which modulates the current flowing through the ultrasonictransducer. As the current flowing through the ultrasonic transducerproduces changes in ultrasonic backscatter detected by the externaltransceiver, temperature can be measured using the implantable devicecomprising the temperature sensor. The implantable device comprising atemperature sensor can be used, for example, to monitor temperature ofan organ (such as the liver, stomach, small or large intestine, kidney,pancreas, gallbladder, bladder, ovaries, uterus, spleen, etc.) in asubject, for example during ablation (e.g., radiofrequency ablation,microwave thermotherapy ablation, or cryotherapy ablation) of tissue,such as a cancer. In some embodiments, the organ is a transplantedorgan. In some embodiments, the implantable device comprising atemperature sensor is used to monitor the temperature of a site ofinfection. In some embodiments, the implantable device with atemperature sensor is able to resolve a temperature within about 2° C.or less (such as within about 1° C. or less, or within about 0.5° C. orless).

FIG. 12A illustrates one embodiment of an implantable device with aminiaturized ultrasonic transducer 1202 (such as a bulk piezoelectrictransducer, a PMUT, or a CMUT) and a temperature sensor 1204 (such as aPTAT circuit or a thermistor). Ultrasonic waves transmitted by aninterrogator vibrate the miniaturized ultrasonic transducer 1202, whichgenerates a current that passes through the temperature sensor 1204. Thetemperature sensor 1204 generates a resistance depending on thetemperature of the sensor 1204, which modulates the current flowingthrough the miniaturized ultrasonic transducer 1202. The ultrasonicbackscatter transmitted by the miniaturized ultrasonic transducer 1202to the interrogator depends on the sensor impedance and the resultantchange in transducer current. Thus, the ultrasonic backscatter dependson the temperature of the temperature sensor 1204, which can be used todetermine the temperature of the surrounding tissue.

FIG. 12B illustrates an embodiment of an implantable device with aminiaturized ultrasonic transducer 1206 (such as a bulk piezoelectrictransducer, a PMUT, or a CMUT), a temperature sensor 1208 (such as aPTAT circuit or a thermistor), and an ASIC 1210. The ASIC 1210 caninclude a digital circuit 1212, which can operate and receive signalsfrom the temperature sensor 1208. The digital circuit 1212 can alsoconvert an analog signal from the temperature sensor 1208 into a digitalsignal. The digital circuit 1212 operates a modulation circuit 1214(such as a switch, for example a FET), which is connected to theminiaturized ultrasonic transducer 1206. The digital circuit 1212 cantransmit a signal to the modulation circuit 1214 a digital signal or ananalog signal, and the modulation circuit 1214 alters the impedance ofcurrent flowing to the miniaturized ultrasonic transducer 1206. In someembodiments, the digital circuit 1212 computes the temperature detectedby the temperature sensor 1208, which is encoded on the signaltransmitted to the modulation circuit 1214. In some embodiments, thedigital circuit 1212 transmits the raw signal from the temperaturesensor 1208 to the modulation circuit 1214. The miniaturized fultrasonic transducer 1206 emits a backscatter ultrasonic wave, whichencodes the temperature information. The ASIC 1210 can also include apower circuit 1216, which can provide power to components of the ASIC;the power circuit derives power from the transducer. Optionally, theASIC can include a driver and/or a front end (such as a CMOS front end),which can be used to control and collect signals from the temperaturesensor 1208.

In some embodiments, the sensor is a pressure sensor. An implantabledevice comprising a pressure sensor can be used, for example, formonitoring blood pressure, pulse rate, tissue inflammation, vascularconstriction, compartment syndrome, gastrointestinal (GI) tractmonitoring, wound recovery, intra-ocular pressure, or cranial pressure.The implantable device can include a miniaturized ultrasonic transducer(such as a bulk piezoelectric transducer, a PMUT, or a CMUT) and apressure sensor. In some embodiments, the implantable device furthercomprises an ASIC (which optionally includes a front end, such as a CMOSfront end, or a driver), which may be integrated with or distinguishablefrom the pressure sensor. In some embodiments, the ASIC includes adigital circuit, a modulation circuit, or a power circuit. In someembodiments, the implantable device does not include an ASIC. Thepressure sensor can be, for example, a microelectromechanical system(MEMS), which can modulate current (which may pass through the ASIC, ifpresent) in response to applied pressure.

FIG. 13A illustrates one embodiment of an implantable device with aminiaturized ultrasonic transducer 1302 (such as a bulk piezoelectrictransducer, a PMUT, or a CMUT) and a pressure sensor 1304 (such as aMEMS). Ultrasonic waves transmitted by an interrogator vibrate theminiaturized ultrasonic transducer 1302, which generates a current thatpasses through the pressure sensor 1304. The pressure sensor 1304exhibits a pressure-dependent impedance 1304, which modulates thecurrent returning to the miniaturized ultrasonic transducer 1302. Theultrasonic backscatter transmitted by the miniaturized ultrasonictransducer 1302 to the interrogator depends on the returning current.Thus, the ultrasonic backscatter depends on the pressure sensed by thepressure sensor 1304, which can be used to determine the pressure of thesurrounding tissue.

FIG. 13B illustrates an embodiment of an implantable device with aminiaturized ultrasonic transducer 1306 (such as a bulk piezoelectrictransducer, a PMUT, or a CMUT), a pressure sensor 1308 (such as a MEMS),and an ASIC 1310. The ASIC 1310 can include a digital circuit 1312,which can operate and receive signals from the pressure sensor 1308. Thedigital circuit 1312 can also convert an analog signal from the pressuresensor 1308 into a digital signal. The digital circuit 1312 operates amodulation circuit 1314 (such as a switch, for example a FET), which isconnected to the miniaturized ultrasonic transducer 1306. The digitalcircuit 1312 can transmit a signal to the modulation circuit 1314 adigital signal or an analog signal, and the modulation circuit 1314alters the impedance presented to the miniaturized ultrasonic transducer1306. In some embodiments, the digital circuit 1312 computes thepressure detected by the pressure sensor 1308, which is encoded on thesignal transmitted to the modulation circuit 1314. In some embodiments,the digital circuit 1312 transmits the raw signal from the pressuresensor 1208 to the modulation circuit 1314. The miniaturized ultrasonictransducer 1306 emits a backscatter ultrasonic wave, which encodes thepressure information. The ASIC 1310 can also include a power circuit1316, which can provide power to components of the ASIC; the powercircuit derives power from the transducer. Optionally, the ASIC caninclude a driver and/or a front end (such as a CMOS front end), whichcan be used to control and collect signals from the pressure sensor1308.

In some embodiments, the sensor is a glucose sensor. Diabetes is a groupof metabolic diseases in which the blood sugar levels are elevated forlong periods of time, resulting in dehydration, cardiovascular damage,nerve damage, and more. Currently there is no cure for diabetes, andthose who suffer from the disease must constantly monitor their bloodglucose levels, as careful regulation of glucose conditions can controldiabetic complications. Conventional glucose monitoring is performed bypatients using a lancet to draw blood and running the blood samplethrough a glucose monitor. This is un-pleasant for patients andpurchasing lancets and test strips can become quite costly, sincediabetic patients must monitor their glucose levels six to seven times aday. Alternate methods of glucose monitoring attempt to address theissue of repeated needle insertion by creating continuous glucosemonitors, but these are either more expensive and still require needleinsertion, or are non-invasive but less accurate. Here, the describedimplantable devices can play a role in continuous glucose monitoring; achronically implanted device in which the backscatter is modulated byglucose oxidation, could allow for continuous glucose monitoring just bypatching an interrogator with conductive gel over the body.

Electrochemical glucose monitoring has been long implemented withamperometric measurements using electrodes coated with enzymes such asglucose oxidase to ensure specificity. Unfortunately, such devices tendto have low device lifetimes. Commercially purchased subcutaneouscontinuous glucose monitors often only have 3-7 day lifetimes due to theinstability of the enzyme layer at body temperatures. To counteractthis, non-enzymatic probes have been developed, such as potentiometricchemical sensors. Unfortunately, one of the leading causes for failureof these devices is simply the introduction of foreign bodies intosubcutaneous tissue. The issue of foreign body response is similar tothe challenge faced in chronic neural interface implantation. Theimplantable devices described herein, such as implantable devices coatedin SiC, provide a powerful solution.

In some embodiments, the implantable device comprises a miniaturizedultrasonic transducer (such as a bulk piezoelectric transducer, a PMUT,or a CMUT), an ASIC, and a glucose sensor. The glucose sensor can detectglucose in blood or interstitial fluid, and the current flowing from thesensor can depend on the concentration of glucose detected by thesensor. Backscatter ultrasonic waves emitted by the miniaturizedultrasonic transducer can encode glucose concentration information. Forexample, the glucose sensor can have a first electrode and a secondelectrode, and a voltage differential can be generated based on theamount of glucose in the sensor. In some embodiments, the firstelectrode is functionalized by glucose oxidase. In some embodiments, thesensor includes a glucose-permeable membrane separating the electrodesfrom the surrounding tissue. In some embodiments, the ASIC includes afront end (such as a CMOS front end) or a driver. In some embodiments,the ASIC includes a digital circuit, a modulation circuit, or a powercircuit. The ASIC can operate the glucose sensor to receive a signaldependent on the concentration of glucose in the sensor. For example,cyclic voltammetry can be used to generate a voltage dependent on theconcentration of glucose, which is reflected in a signal received by theAISC. In some embodiments, the digital circuit operates the glucosesensor. The signal from the glucose sensor is sent to a modulationcircuit (such as a switch, for example a FET), would modulates theimpedance presented to the miniaturized ultrasonic transducer. In someembodiments, the digital circuit controls the modulation circuit. Insome embodiments, the digital circuit can transmits a raw signal to themodulation circuit. In some embodiments, the digital circuit determinesthe glucose concentration from the raw signal received from the glucosesensor, and sends a signal to the modulation circuit encoding thedetermined glucose concentration.

In some embodiments, the sensor is a strain sensor (or strain gauge).The strain sensor measures how much a material (such as a tissue ororgan) stretches in proportion to a baseline length. A strain sensor caninclude, for example, a thin film conductor or semiconductor thatchanges resistance as it stretches.

Manufacture of an Implantable Device

The implantable devices can be manufactured by attaching a miniaturizedultrasonic transducer (such as a CMUT, a PMUT, or a bulk piezoelectrictransducer) to a first electrode on a first face of the piezoelectrictransducer, and a second electrode to a second face of the piezoelectrictransducer, wherein the first face and the second face are on oppositesides of the piezoelectric transducer. The first electrode and thesecond electrode can be attached to an application-specific integratedcircuit (ASIC), which may be disposed on a printed circuit board (PCB).Attachment of the components to the PCB can include wirebonding,soldering, flip-chip bonding, or gold bump bonding. The ASIC can includeone or more sensors.

Certain piezoelectric materials can be commercially obtained, such asmetalized PZT sheets of varying thickness (for example, PSI-5A4E, PiezoSystems, Woburn, Mass., or PZT 841, APC Internationals, Mackeyville,Pa.). In some embodiments, a piezoelectric material sheet is diced intoa desired size, and the diced piezoelectric material is attached to theelectrodes. In some embodiments, the electrodes are attached to thepiezoelectric material sheet, and the piezoelectric material sheet isdiced to the desired size with the electrodes attached to thepiezoelectric material. The piezoelectric material can be diced using adicing saw with a ceramic blade to cut sheets of the piezoelectricmaterial into individualized piezoelectric transducer. In someembodiments, a laser cutter is used to dice or singulate thepiezoelectric material. In some embodiments, patterned etching is usedto dice or singulate the piezoelectric material.

Electrodes can be attached to the top and bottom of the faces of thepiezoelectric transducers, with the distance between the electrodesbeing defined as the height of the piezoelectric transducer. Exemplaryelectrodes can comprise one or more of silver, gold, platinum,platinum-black, poly(3,4-ethylenedioxythiophene (PEDOT), a conductivepolymer (such as conductive PDMS or polyimide), or nickel. In someembodiments, the electrode is attached to the piezoelectric transducerby electroplating or vacuum depositing the electrode material onto theface of the piezoelectric transducer. In some embodiments, theelectrodes are soldered onto the piezoelectric transducer using anappropriate solder and flux. In some embodiments, the electrodes areattached to the piezoelectric transducer using an epoxy (such as asilver epoxy) or low-temperature soldering (such as by use of a solderpaste).

In an exemplary embodiment, solder paste is applied to a pad on aprinted circuit board (PCB), either before or after the ASIC is attachedto the PCB. The size of the pad on the circuit board can depend on thedesired size of the piezoelectric transducer. Solely by way of example,if the desired size of piezoelectric transducer is about 100 μm×100μm×100 μm, the pad can be about 100 μm×100 μm. The pad functions as thefirst electrode for the implantable device. A piezoelectric material(which may be larger than the pad) is placed on the pad, and is held tothe pad by the applied solder paste, resulting in a piezoelectric-PCBassembly. The piezoelectric-PCB assembly is heated to cure the solderpaste, thereby bonding the piezoelectric transducer to the PCB. If thepiezoelectric material is larger than the pad, the piezoelectricmaterial is cut to the desired size, for example using a wafer dicingsaw or a laser cutter. Non-bonded portions of the piezoelectric material(for example, the portions of the piezoelectric material that did notoverlay the pad) are removed. A second electrode is attached to thepiezoelectric transducer and the PCB, for example by forming a wirebondbetween the top of the piezoelectric transducer and the PCB, whichcompletes the circuit. The wirebond is made using a wire made from anyconductive material, such as aluminum, copper, silver, or gold.

The integrated circuit and the miniaturized ultrasonic transducer can beattached on the same side of the PCB or on opposite sides of the PCB. Insome embodiments, the PCB is a flexible PCB, the integrated circuit andthe ultrasonic transducer are attached to the same side of the PCB, andthe PCB is folded, resulting in an implantable device in which theintegrated circuit and the ultrasonic transducer are on opposite sidesof the PCB.

Optionally, the device or a portion of the device is encapsulated in abiocompatible material (such as a biocompatible polymer), for example acopolymer of N-vinyl-2-pyrrolidinone (NVP) and n-butylmethacrylate(BMA), polydimethylsiloxane (PDMS, e.g., Sylgard 184, Dow Corning,Midland, Mich.), parylene, polyimide, silicon nitride, silicon dioxide,alumina, niobium, hydroxyapatite, or silicon carbide. The siliconcarbide can be amorphous silicon carbide or crystalline silicon carbide.In some embodiments, the biocompatible material (such as amorphoussilicon carbide) is applied to the device by plasma enhanced chemicalvapor deposition (PECVD) or sputtering. PECVD may use precursors such asSiH₄ and CH₄ to generate the silicon carbide. In some embodiments, theimplantable device or portion of the implantable device is encased in aceramic (for example, alumina or titania) or a metal (for example, steelor titanium) suitable for medical implantation.

FIG. 14 illustrates an exemplary method of producing the implantabledevice described herein. At step 1402, an ASIC is attached to a PCB. Asolder (such as a silver epoxy) can be applied to the PCB (for example,at a first pad disposed on the PCB), and the ASIC can be placed on thesolder. The solder can be cured, for example by heating the PCB with theASIC. In some embodiments, the PCB with the ASIC is heated to about 50°C. to about 200° C., such as about 80° C. to about 170° C., or about150° C. In some embodiments, the PCB with the ASIC is heated for about 5minutes to about 600 minutes, such as about 10 minutes to about 300minutes, about 10 minutes to about 100 minutes, about 10 minutes toabout 60 minutes, about 10 minutes to about 30 minutes, or about 15minutes. Optionally, the ASIC is coated with additional solder. At step1404, a piezoelectric transducer (the “piezo” in FIG. 14) is attached tothe PCB. A solder (such as a silver epoxy) can be applied to the PCB(for example, at a second pad disposed on the PCB), and a piezoelectricmaterial can be placed on the solder. The piezoelectric material can bea fully formed (i.e., “diced”) piezoelectric transducer, or can be apiezoelectric material sheet that is cut to form the piezoelectrictransducer once attached to the PCB. The solder can be cured, forexample by heating the PCB with the piezoelectric material. In someembodiments, the PCB with the piezoelectric material is heated to about50° C. to about 200° C., such as about 80° C. to about 170° C., or about150° C. In some embodiments, the PCB with the piezoelectric material isheated for about 5 minutes to about 600 minutes, such as about 10minutes to about 300 minutes, about 10 minutes to about 100 minutes,about 10 minutes to about 60 minutes, about 10 minutes to about 30minutes, or about 15 minutes. The piezoelectric material can be cutusing a saw or laser cutter to the desired dimensions. In someembodiments, the piezoelectric material is a solgel (such as a PZTsolgel) and the transducer material can be shaped with deep reactive ionetching (DRIE). Although FIG. 14 illustrates attachment of the ASIC tothe PCB at step 1402 prior to attachment of the piezoelectric materialto the PCB at step 1404, a person of skill in the art will appreciatethat the ASIC and the piezoelectric material can be attached in anyorder. At step 1406, the ASIC and the piezoelectric transducer arewirebonded to the PCB. Although the method illustrated in FIG. 14 showsthe ASIC and the piezoelectric transducer to the PCB after the ASIC andthe piezoelectric transducer are attached to the PCB, a person of skillin the art will appreciate that the ASIC can be wirebonded to the PCBafter the ASIC is attached to the PCB, and can be wirebonded eitherbefore or after attachment of the piezoelectric transducer. Similarly,the piezoelectric transducer may be wirebonded to the PCB either beforeor after attachment or wirebonding of the ASIC to the PCB. At step 1408,a sensor is attached to the PCB. The sensor can be any sensor describedherein. A solder (such as a silver epoxy) can be applied to the PCB (forexample, at a third pad disposed on the PCB), and the sensor can beplaced on the solder. The solder can be cured, for example by heatingthe PCB with the sensor. In some embodiments, the PCB with the sensor isheated to about 50° C. to about 200° C., such as about 80° C. to about170° C., or about 150° C. In some embodiments, the PCB with the sensoris heated for about 5 minutes to about 600 minutes, such as about 10minutes to about 300 minutes, about 10 minutes to about 100 minutes,about 10 minutes to about 60 minutes, about 10 minutes to about 30minutes, or about 15 minutes. Although FIG. 14 illustrates the sensorbeing attached the PCB after the piezoelectric transducer and the ASICare attached to the PCB, a person of skill in the art would understandthat the sensor can be attached to the PCB either before or after theASIC and the piezoelectric transducer are attached to the PCB. Dependingon the sensor type, the sensor may be wirebonded to the PCB, which mayoccur after the sensor is attached to the PCB, and either before orafter wirebonding of the piezoelectric transducer and/or ASIC to thePCB. At step 1410, at least a portion of the device is coated with abiocompatible material. Preferably, at least the piezoelectrictransducer and the ASIC are coated with the biocompatible material. Insome embodiments, the sensor is not or at least a portion of the sensoris not coated with the biocompatible material. For example, in someembodiments, the sensor comprises a pair of electrodes which are notcoated with the biocompatible material, which allows the electrodes todetect changes in a physiological condition. In some embodiments, thebiocompatible material is cured, for example by exposure to UV light orby heating.

In some embodiments, the implantable device is encapsulated in anamorphous silicon carbide (a-SiC) film. FIG. 15 illustrates a method ofmanufacturing an implantable device encapsulated in an a-SiC film. Atstep 1502, a polyimide layer is applied to a smooth surface. At step1504, an a-SiC layer is applied to the polyimide layer. This can bedone, for example, using plasma enhanced chemical vapor deposition(PECVD), using SiH₄ and CH₄ as precursors. At step 1506, one or moreports are etched into the a-SiC layer. In some embodiments, ports arealso etched into the polyimide layer. The ports provide access forportions of the implantable device that are not encapsulated by thea-SiC, such as portions of a sensor or an electrode that will contactthe tissue, blood, or interstitial fluid after implant. In someembodiments, etching comprises reactive-ion etching. At step 1508, theimplantable device is attached to the a-SiC layer. The implantabledevice may be pre-assembled before being attached to the a-SiC layer, ormay be built on the a-SiC. In some embodiments, a printed circuit board(PCB), miniaturized ultrasonic transducer, and sensor are attached tothe a-SiC layer. The miniaturized ultrasonic transducer and the sensorneed not come in direct contact with the a-SiC layer, as they may beattached to the PCB. Attachment of miniaturized ultrasonic transducer orsensor to the PCB may occur before or after attachment of the PCB to thea-SiC layer. In some embodiments, attachment of miniaturized ultrasonictransducer or sensor to the PCB comprises wirebonding the miniaturizedultrasonic transducer or sensor to the PCB. In some embodiments, thesensor includes a portion that interfaces with the ports etched into thea-SiC layer. In some embodiments, an ASIC is attached to the PCB, whichmay occur before or after attachment of the PCB to the a-SiC layer. Atstep 1510, an exposed portion of the implantable device is coated withan a-SiC layer. In some embodiments, the exposed portion of theimplantable device is coated with an a-SiC layer using PECVD. At step1512, the encapsulated implantable device is embossed, thereby releasingthe implantable device from the SiC layer.

EXEMPLARY EMBODIMENTS Embodiment 1

An implantable device, comprising:

-   -   a sensor configured to detect an amount of an analyte, pH, a        temperature, a strain, or a pressure; and    -   an ultrasonic transducer with a length of about 5 mm or less in        the longest dimension, configured to receive current modulated        based on the analyte amount, the pH, the temperature, or the        pressure detected by the sensor, and emit an ultrasonic        backscatter based on the received current.

Embodiment 2

The implantable device of embodiment 1, wherein the ultrasonictransducer is configured to receive ultrasonic waves that power theimplantable device.

Embodiment 3

The implantable device of embodiment 2, wherein the ultrasonictransducer is configured to receive ultrasonic waves from aninterrogator comprising one or more ultrasonic transducers.

Embodiment 4

The implantable device of any one of embodiments 1-3, wherein theultrasonic transducer is a bulk piezoelectric transducer.

Embodiment 5

The implantable device of embodiment 4, wherein the bulk ultrasonictransducer is approximately cubic.

Embodiment 6

The implantable device of any one of embodiments 1-5, wherein theultrasonic transducer is a piezoelectric micro-machined ultrasonictransducer (PMUT) or a capacitive micro-machined ultrasonic transducer(CMUT).

Embodiment 7

The implantable device of any one of embodiments 1-6, wherein theimplantable device is about 5 mm or less in length in the longestdimension.

Embodiment 8

The implantable device of any one of embodiments 1-7, wherein the volumeof the implantable device is about 5 mm3 or less.

Embodiment 9

The implantable device of any one of embodiments 1-8, wherein the volumeof the implantable device is about 1 mm3 or less.

Embodiment 10

The implantable device of any one of embodiments 1-9, wherein theimplantable device is implanted in a subject.

Embodiment 11

The implantable device of embodiment 10, wherein the subject is ananimal.

Embodiment 12

The implantable device of embodiment 10 or 11, wherein the subject is ahuman.

Embodiment 13

The implantable device of embodiment 10, wherein the subject is a plant.

Embodiment 14

The implantable device of any one of embodiments 1-3, wherein the sensordetects the amount of the analyte or pH.

Embodiment 15

The implantable device of embodiment 14, wherein the sensor is anoptical sensor.

Embodiment 16

The implantable device of embodiment 15, wherein the optical sensorcomprises a light source and an optical detector.

Embodiment 17

The implantable device of embodiment 15 or 16, wherein the opticalsensor detects blood pressure or a pulse.

Embodiment 18

The implantable device of embodiment 15 or 16, wherein the opticalsensor comprises a matrix comprising a fluorophore, and whereinfluorescence intensity or fluorescence lifetime of the fluorophoredepends on the amount of the analyte.

Embodiment 19

The implantable device of any one of embodiments 15, 16, or 18, whereinthe sensor detects pH or oxygen.

Embodiment 20

The implantable device of embodiment 15 or 16, wherein the opticalsensor is configured to perform near-infrared spectroscopy.

Embodiment 21

The implantable device of embodiment 20, wherein the sensor detectsglucose.

Embodiment 22

The implantable device of any one of embodiments 16-21, wherein theoptical sensor comprises an optical filter on the light source or on theoptical detector.

Embodiment 23

The implantable device of anyone of embodiments 16-22, wherein theoptical sensor comprises an optical filter on the light source and theoptical detector.

Embodiment 24

The implantable device of any one of embodiments 1-13, wherein thesensor is a potentiometric chemical sensor.

Embodiment 25

The implantable device of any one of embodiments 1-13, wherein thesensor is an amperometric chemical sensor.

Embodiment 26

The implantable device of embodiment 24 or 25, wherein the sensordetects oxygen, pH, or glucose.

Embodiment 27

The implantable device of any one of embodiments 1-13, wherein thesensor is a temperature sensor.

Embodiment 28

The implantable device of embodiment 27, wherein the temperature sensoris a thermistor, a thermocouple, or a proportional to absolutetemperature (PTAT) circuit.

Embodiment 29

The implantable device of any one of embodiments 1-13, wherein theimplantable device comprises a bulk piezoelectric ultrasonic transducerand a thermistor.

Embodiment 30

The implantable device of embodiment 1, wherein the sensor is a pressuresensor.

Embodiment 31

The implantable device of embodiment 30, wherein the pressure sensor ismicroelectromechanical system (MEMS) sensor.

Embodiment 32

The implantable device of embodiment 30 or 31, wherein the implantabledevice is configured to measure blood pressure or a pulse.

Embodiment 33

The implantable device of any one of embodiments 1-32, wherein theimplantable device further comprises an integrated circuit.

Embodiment 34

The implantable device of embodiment 33, wherein the integrated circuitcomprises a power circuit.

Embodiment 35

The implantable device of embodiments 33 or 34, wherein the integratedcircuit comprises a driver configured to provide current to the sensor.

Embodiment 36

The implantable device of any one of embodiments 33-35, wherein theintegrated circuit comprises a driver configured to provide current toone or more light sources.

Embodiment 37

The implantable device of any one of embodiments 34-36, wherein theintegrated circuit comprises a front end configured to receive a signalfrom the sensor.

Embodiment 38

The implantable device of any one of embodiments 34-37, wherein theintegrated circuit comprises a front end configured to receive a signalfrom a light detector.

Embodiment 39

The implantable device of embodiment 37 or 38, wherein the front end isa CMOS front end.

Embodiment 40

The implantable device of any one of embodiments 33-39, wherein theintegrated circuit comprises a modulation circuit comprising a switch.

Embodiment 41

The implantable device of embodiment 40, wherein the switch comprises afield effect transistor (FET).

Embodiment 42

The implantable device of any one of embodiments 33-41, wherein theintegrated circuit comprises an analog-to-digital converter (ADC).

Embodiment 43

The implantable device of any one of embodiments 33-42, wherein theintegrated circuit comprises a digital circuit.

Embodiment 44

The implantable device of embodiment 43, wherein the digital circuit isconfigured to operate a modulation circuit.

Embodiment 45

The implantable device of embodiment 43 or 44, wherein the digitalcircuit is configured to transmit a digitized signal to the modulationcircuit, wherein the digitized signal is based on the detected amount ofthe analyte, the temperature, or the pressure.

Embodiment 46

The implantable device of any one of embodiments 1-45, wherein theimplanted device is at least partially encapsulated by a biocompatiblematerial.

Embodiment 47

The implanted device of embodiment 46, wherein the biocompatiblematerial is a copolymer of N-vinyl-2-pyrrolidinone (NVP) andn-butylmethacrylate (BMA), polydimethylsiloxane (PDMS), parylene,polyimide, silicon nitride, silicon dioxide, alumina, niobium,hydroxyapatite, silicon carbide, titania, steel, or titanium.

Embodiment 48

The implanted device of embodiment 46, wherein the biocompatiblematerial comprises a ceramic or a metal.

Embodiment 49

The implantable device of any one of embodiments 1-48, wherein theimplantable device further comprises a non-responsive reflector.

Embodiment 50

The implantable device of any one of embodiments 1-49, wherein theimplantable device comprises two or more sensors.

Embodiment 51

A system comprising one or more implantable devices according to any oneof embodiments 1-50 and an interrogator comprising one or moreultrasonic transducers configured to transmit ultrasonic waves to theone or more implantable devices or receive ultrasonic backscatter fromthe one or more implantable devices.

Embodiment 52

The system of embodiment 51, wherein the interrogator comprises a firstultrasonic transducer configured to transmit ultrasonic waves and asecond ultrasonic transducer configured to receive ultrasonicbackscatter from the one or more implantable devices.

Embodiment 53

The system of embodiment 51 or 52, wherein the interrogator comprisestwo or more separate interrogator devices, wherein a first interrogatordevice is configured to transmit ultrasonic waves to the one or moreimplantable devices and a second interrogator device is configured toreceive ultrasonic backscatter from the one or more implantable devices.

Embodiment 54

The system according to any one of embodiments 51-53, wherein theinterrogator comprises two or more ultrasonic transducer arrays, whereineach transducer array comprises two or more ultrasonic transducers.

Embodiment 55

The system according to any one of embodiments 51-54, wherein at leastone of the one or more ultrasonic transducers is configured toalternatively transmit ultrasonic waves to the one or more implantabledevices or receive ultrasonic backscatter from the one or moreimplantable devices, wherein the configuration of the transducer iscontrolled by a switch on the interrogator.

Embodiment 56

The system according to any one of embodiments 51-55, wherein the systemcomprises a plurality of implantable devices.

Embodiment 57

The system of embodiment 56, wherein the interrogator is configured tobeam steer transmitted ultrasonic waves to alternatively focus thetransmitted ultrasonic waves on a first portion of the plurality ofimplantable devices or focus the transmitted ultrasonic waves on asecond portion of the plurality of implantable devices.

Embodiment 58

The system of embodiment 56, wherein the interrogator is configured tosimultaneously receive ultrasonic backscatter from at least twoimplantable devices.

Embodiment 59

The system of embodiment 56, wherein the interrogator is configured totransit ultrasonic waves to the plurality of implantable devices orreceive ultrasonic backscatter from the plurality of implantable devicesusing time division multiplexing.

Embodiment 60

The system of embodiment 56, wherein the interrogator is configured totransit ultrasonic waves to the plurality of implantable devices orreceive ultrasonic backscatter from the plurality of implantable devicesusing spatial multiplexing.

Embodiment 62

The system of embodiment 56, wherein the interrogator is configured totransit ultrasonic waves to the plurality of implantable devices orreceive ultrasonic backscatter from the plurality of implantable devicesusing frequency multiplexing.

Embodiment 63

The system according to any one of embodiments 51-62, wherein theinterrogator is configured to be wearable by a subject.

Embodiment 64

A method of detecting an amount of an analyte, a pH, a temperature, or apressure, comprising:

-   -   receiving ultrasonic waves that power one or more implantable        devices comprising an ultrasonic transducer with a length of        about 5 mm or less in the longest dimension;    -   converting energy from the ultrasonic waves into an electrical        current;    -   transmitting the electrical current to a sensor configured to        measure the amount of the analyte, the pH, the temperature, or        the pressure;    -   modulating the electrical current based on the measured amount        of the analyte, pH, temperature, or pressure;    -   transducing the modulated electrical current into an ultrasonic        backscatter that encodes the measured amount of the analyte, pH,        temperature, or pressure; and    -   emitting the ultrasonic backscatter to an interrogator        comprising one or more transducer configured to receive the        ultrasonic backscatter.

Embodiment 65

A method of detecting an amount of an analyte, a pH, a temperature, or apressure, comprising:

-   -   receiving ultrasonic waves that power one or more implantable        devices comprising an ultrasonic transducer with a length of        about 5 mm or less in the longest dimension;    -   converting energy from the ultrasonic waves into an electrical        current;    -   measuring the amount of the analyte, the pH, the temperature, or        the pressure using a sensor;    -   modulating the electrical current based on the measured amount        of the analyte, pH, temperature, or pressure;    -   transducing the modulated electrical current into an ultrasonic        backscatter that encodes the measured amount of the analyte, pH,        temperature, or pressure; and    -   emitting the ultrasonic backscatter to an interrogator        comprising one or more transducer configured to receive the        ultrasonic backscatter.

Embodiment 66

The method of embodiment 64 or 65, further comprising receiving theultrasonic backscatter using the interrogator.

Embodiment 67

The method of any one of embodiments 64-66, further comprisingtransmitting the ultrasonic waves using the interrogator configured totransmit the ultrasonic waves.

Embodiment 68

The method of embodiment 67, wherein the ultrasonic waves aretransmitted in two or more pulses.

Embodiment 69

The method of any one of embodiments 64-68, comprising analyzing theultrasonic backscatter to determine the measured amount of the analyte,pH, temperature, or pressure.

Embodiment 70

The method of any one of embodiments 64-69, wherein the method comprisesmeasuring the amount of the analyte or pH.

Embodiment 71

The method of any one of embodiments 64-70, wherein the methodcomprising measuring an amount of oxygen or pH.

Embodiment 72

The method of any one of embodiments 64-71, wherein the method comprisesmonitoring tissue oxygenation levels.

Embodiment 73

The method of embodiment 72, wherein the one or more implantable devicesare implanted on, within, or proximal to a blood vessel, implantedorgan, or a tumor.

Embodiment 74

The method of any one of embodiments 64-73, comprising emitting lightand detecting fluorescence intensity or fluorescence lifetime, whereinthe fluorescence intensity or fluorescence lifetime depends on theamount of the analyte or the pH.

Embodiment 75

The method of embodiment 74, comprising determining a phase shiftbetween oscillating emitted light and detected fluorescence isdetermined, wherein the phase shift depends on the amount of the analyteor the pH.

Embodiment 76

The method of embodiment 74 or 75, comprising determining a fluorescentlifetime for the detected fluorescence resulting from pulsed oroscillating emitted light.

Embodiment 77

The method of any on one of embodiments 64-70, wherein the methodcomprises measuring an amount of glucose.

Embodiment 78

The method of any one of embodiments 64-69, comprising measuring thetemperature.

Embodiment 79

The method of embodiment 78, wherein the one or more implantable devicesare implanted on, within, or proximal to a blood vessel, implantedorgan, or a tumor.

Embodiment 80

The method of embodiment 78 or 79, comprising monitoring temperature ofan organ or a site of an infection.

Embodiment 81

The method of any one of embodiments 64-69, comprising measuring thepressure.

Embodiment 82

The method of embodiment 81, comprising measuring a pulse rate or ablood pressure.

Embodiment 83

The method of any one of embodiments 64-82, comprising determining arelative location of the one or more implantable devices.

Embodiment 84

The method of any one of embodiments 53-83, comprising detecting angularor lateral movement of the one or more implantable devices.

Embodiment 85

The method of embodiment 84, comprising analyzing the ultrasonicbackscatter to determine the measured amount of the analyte, thetemperature, or the pressure, wherein the analysis comprises accountingfor angular or lateral movement of the implantable device.

Embodiment 86

The method of any one of embodiments 64-85, comprising implanting theimplantable device in a subject.

Embodiment 87

The method of embodiment 86, wherein the subject is an animal.

Embodiment 88

The method of embodiment 86 or 87, wherein the subject is a human.

Embodiment 89

The method of embodiment 86, wherein the subject is a plant.

Embodiment 90

The method of any one of embodiments 64-89, wherein the ultrasonicbackscatter encodes a digitized signal.

Embodiment 91

The method of any one of embodiments 64-90, comprising receiving theultrasonic backscatter.

Embodiment 92

The method of embodiment 91, wherein the ultrasonic backscatter isreceived from a plurality of implantable devices.

Embodiment 93

The method of embodiment 92, wherein the ultrasonic backscatter isreceived from the plurality of implantable devices using time divisionmultiplexing.

Embodiment 94

The method of embodiment 92, wherein the ultrasonic backscatter isreceived from the plurality of implantable devices using spatialmultiplexing.

Embodiment 95

The method of embodiment 92, wherein the ultrasonic backscatter isreceived from the plurality of implantable devices using frequencymultiplexing.

Embodiment 96

A medical system comprising:

-   -   an ultrasound transceiver configured to generate ultrasound        interrogation pulses at an adjustable at least one of frequency,        amplitude, phase and duty cycle, and receive ultrasound        backscatter produced by transmitted ultrasound interrogation        pulses; and    -   an implantable device comprising leads to sense a body        condition, and circuitry to reflect received ultrasound        interrogation pulses modulated based upon a body condition        sensed by the leads.

Embodiment 97

The medical system of embodiment 96, wherein the ultrasound transceiveris implantable, and is further configured to communicate wirelessly withan external transceiver.

Embodiment 98

The medical system of any of embodiments 96-97, wherein the at least oneof frequency, amplitude, phase and duty cycle of generated ultrasoundinterrogation pulses is adjustably set based upon a determined distancebetween an ultrasound transceiver and the implantable device.

Embodiment 99

The medical system of embodiment 98, wherein the at least one offrequency, amplitude, phase and duty cycle corresponds to a focal lengthof ultrasound transmissions suitable given the determined distancebetween an ultrasound transceiver and the implantable device.

Embodiment 100

The medical system of any of embodiments 98-99, wherein the system isconfigured to determine the distance between an ultrasound transceiver.

Embodiment 101

The medical system of any of embodiments 97-100, wherein the distancedetermination is made by an external transceiver.

Embodiment 102

A medical system comprising:

-   -   an ultrasound transceiver configured to generate ultrasound        interrogation pulses and receive ultrasound backscatter produced        by transmitted ultrasound interrogation pulses; and    -   an implantable device comprising leads to sense a biological        condition, at least one responsive region responsive to a sensed        biological condition sensed by the leads, and at least one        non-responsive region that is not responsive to the sensed        biological condition, the implantable device reflects received        ultrasound interrogation pulses producing a particular pulse        signature with at least one portion of the signature        corresponding to the at least one responsive region at least one        other portion of the signature corresponding to the at least one        non-responsive region.

Embodiment 103

The medical system of embodiment 102, wherein the system comprises aplurality of the implantable devices with different configurations ofthe responsive and non-responsive regions, to produce a different pulsesignatures.

Embodiment 104

The medical system of embodiment 103, wherein the pulse signature isused by the system to determine an identity of the implantable devicethat produced an ultrasound reflection.

Embodiment 105

A medical system comprising:

-   -   an ultrasound transceiver comprising an array of transducers        each configured to generate ultrasound interrogation pulses,        each transducer comprising one of a micro-machined structure and        bulk piezo crystal, the transceiver further configured to        receive ultrasound backscatter produced by transmitted        ultrasound interrogation pulses; and    -   multiple implantable devices each comprising leads to sense a        body condition, and circuitry to reflect received ultrasound        interrogation pulses modulated based upon a body condition        sensed by the leads.

Embodiment 106

The medical system of embodiment 105, wherein the ultrasound transceiversteers ultrasound beams generated by the transducers.

Embodiment 107

The medical system of any of embodiments 105 or 106, whereincommunication between the ultrasound transceiver and the multipleimplantable devices uses time division multiplexing.

Embodiment 108

The medical system of any of embodiments 105 or 106, whereincommunication between the ultrasound transceiver and the multipleimplantable devices uses spatial multiplexing.

Embodiment 109

The medical system of any of embodiments 105 or 106, whereincommunication between the ultrasound transceiver and the multipleimplantable devices uses frequency multiplexing.

Embodiment 110

An internal body condition sensing system, comprising:

-   -   an ultrasound transceiver configured to generate ultrasound        transmissions and receive ultrasound backscatter produced by        generated ultrasound transmissions; and    -   a body implantable device comprising an optical sensor to sense        an internal body biologic condition, and comprising an        ultrasound backscatter communication system to modulate in        reflected ultrasound backscatter communications information        indicative of the internal body biologic condition.

Embodiment 111

The internal body biologic condition sensing system of embodiment 110,wherein the body implantable device additionally comprises an opticalemitter.

Embodiment 112

The internal body biologic condition sensing system of embodiment 110,wherein the optical sensor is configured to measure tissue oxygenationlevels.

Embodiment 113

The internal body biologic condition sensing system of any ofembodiments 110 or 111, wherein the optical sensor is configured toperform near-infrared spectroscopy.

Embodiment 114

The internal body biologic condition sensing system of embodiment 110,wherein the optical sensor is configured to measure a blood analyte.

Embodiment 115

The internal body biologic condition sensing system of embodiment 113,wherein the analyte is glucose.

Embodiment 116

The internal body biologic condition sensing system of embodiment 113,wherein the analyte is pH.

Embodiment 117

The internal body biologic condition sensing system of embodiment 110,wherein the optical sensor is configured to measure blood pressure.

Embodiment 118

A method of sensing an internal body biologic condition, comprising:

-   -   implanting at a location of interest a body implantable device        comprising an optical sensor to sense an internal body biologic        condition, the body implantable device further comprising an        ultrasound backscatter communication system to modulate in        reflected biologic condition; and    -   using an ultrasound transceiver configured to generate        ultrasound transmissions and receive ultrasound backscatter        produced by generated ultrasound transmissions, to interrogate        the body implantable device to obtain information indicative of        the sensed internal biologic condition.

Embodiment 119

The method of embodiment 118, wherein the optical sensor is configuredto measure tissue oxygenation levels.

Embodiment 120

The method of embodiment 118, wherein the body implantable device isimplanted in a location at or near a tumor, to monitor tumoroxygenation.

Embodiment 121

The method of embodiment 118, wherein a plurality of ones of the bodyimplantable device are implanted at various locations in the brain, andthe method further comprises performing functional brain imaging theinformation indicative of the sensed internal biologic condition of thebrain.

Embodiment 122

The method of embodiment 118, wherein the optical sensor is configuredto measure a blood analyte.

Embodiment 123

The method of embodiment 122, wherein the analyte is glucose.

Embodiment 124

The method of embodiment 123, wherein the analyte is pH.

Embodiment 125

The method of embodiment 118, wherein the optical sensor is configuredto measure blood pressure.

Embodiment 126

An internal body condition sensing system, comprising:

-   -   an ultrasound transceiver configured to generate ultrasound        transmissions and receive ultrasound backscatter produced by        generated ultrasound transmissions; and    -   a body implantable device comprising a pressure sensor to sense        an internal body biologic condition, and comprising an        ultrasound backscatter communication system to modulate in        reflected ultrasound backscatter communications information        indicative of the internal body biologic condition.

Embodiment 127

An internal body condition sensing system, comprising:

-   -   ultrasound backscatter produced by generated ultrasound        transmissions; and    -   a body implantable device comprising a temperature sensor to        sense an internal body biologic condition, and comprising an        ultrasound backscatter communication system to modulate in        reflected ultrasound backscatter communications information        indicative of the internal body biologic condition.

Embodiment 128

An internal body condition sensing system, comprising:

-   -   an ultrasound transceiver configured to generate ultrasound        transmissions and receive ultrasound backscatter produced by        generated ultrasound transmissions; and    -   a body implantable device comprising a potentiometric chemical        sensor to sense an internal body biologic condition, and        comprising an ultrasound backscatter communication system to        modulate in reflected ultrasound backscatter communications        information indicative of the internal body biologic condition.

Embodiment 129

An internal body condition sensing system, comprising:

-   -   an ultrasound transceiver configured to generate ultrasound        transmissions and receive ultrasound backscatter produced by        generated ultrasound transmissions; and    -   a body implantable device comprising an amperometric chemical        sensor to sense an internal body biologic condition, and        comprising an ultrasound backscatter communication system to        modulate in reflected ultrasound backscatter communications        information indicative of the internal body biologic condition.

EXAMPLES Example 1—Manufacture of an Implantable Device

In short form, the assembly steps of the implantable device are asfollows:

-   -   1. Attach ASIC to PCB.    -   2. Wirebond ASIC ports to PCB.    -   3. Attach piezoelectric element to PCB.    -   4. Wirebond piezoelectric element ports to PCB.    -   5. Encapsulate full device except for recording electrodes.

The ASIC measures 450 μm by 500 μm by 500 μm and is fabricated by TaiwanSemiconductor Manufacturing Company's 65 nm process. Each chip containstwo transistors with 5 ports each: source, drain, gate, center, andbulk. Each FET uses the same bulk, so either bulk pad can be bonded to,but the transistors differ in that the transistor padded out to the toprow does not contain a resistor bias network whereas the transistorpadded out in the bottom row does. The chip additionally containssmaller pads for electroplating. The same process can be applied toASIC's with more complex circuitry and thus more pads. These pads werenot used in this example. Three versions of the FET were taped out:

-   -   Die 1: Long channel FET with threshold voltage: 500 Mv.    -   Die 2: Short channel FET with threshold voltage at 500 mV.    -   Die 3: Native FET with threshold voltage at 0 mV.

Confirmation of electrical characteristics of these FETs were measuredusing a specially designed CMOS characterization board which containedof a set of pads as wirebonding targets and a second set of pads inwhich wires were soldered to. A sourcemeter (2400 Sourcemeter, KeithleyInstruments, Cleveland, Ohio) was used to supply VDS to the FET andmeasure I_(DS). An adjustable power supply (E3631A, Agilent, SantaClara, Calif.) was used to modulate V_(GS) and the I-V characteristicsof the FETs were obtained. Uncharacteristic IV curves for type 2 dieswere consistently measured, and upon impedance measurement, found thatthe short channel of the die 2 s would short out the FET.

The piezoelectric element is lead-zirconium titanate (PZT). It ispurchased as a disc from APC International and diced into. 750 μm×750μm×750 μm cubes using a wafer saw (DAD3240, Disco, Santa Clara, Calif.)with a ceramic blade (PN CX-010-′270-080-H). This mote size was chosenas it maximized power transfer efficiency. For more details, see Seo etal., Neural dust: an ultrasonic, low power solution for chronicbrain-machine interfaces, arXiv: 1307.2196v1 (Jul. 8, 2013).

The implantable device substrate integrates the ASIC with thepiezoelectric element and recording electrodes. The first version of theimplantable device used custom-designed PCBs purchased from TheBoardworks (Oakland, Calif.) as a substrate. The PCBs were made of FR-4and were 30 mil (approximately 0.762 mm) in thickness. The dimensions ofthe board were 3 mm×1 mm. This design was the first attempt anintegrated communication and sense platform, so pad size and spacing waschosen to facilitate assembly at the cost of larger size. To conservePCB real-estate, each face of the PCB included pads for either thepiezoelectric element or the ASIC and its respective connections to thePCB. Additionally, two recording pads were placed on the ASIC-face ofthe board. All exposed electrodes were plated with ENIG by TheBoardworks. The pad for the ASIC to sit on was 500 μm by 500 μm, chosento fit the size of the die. The wirebond target pad size was chosen tobe 200 μm by 200 μm and spaced roughly 200 μm away from the edge of thedie in order to give enough clearance for wirebonding (discussed below).Electrode size and spacing varied and were empirically optimized.

In the second iteration of implantable device, three concerns primaryconcerns were addressed: 1) size, 2) ease of wirebonding, 3)implantation/communication. First, to decrease board thickness the FR-4substrate was replaced with a 2 mil (about 50.8 μm) thick polyimideflexible PCB (AltaFlex, Santa Clara, Calif.), as well as thinning theASIC (Grinding and Dicing Services Inc., San Jose, Calif.) to 100 μm. Tofacilitate bonding, the ASIC and PZT coupon were moved to the same side,with only the recording electrodes on the backside of the substrate.While putting the ASIC and PZT coupon on the same side of the board doesimpose a limit on how much the substrate size can be reduced, spacingbetween the electrodes restricted the board length of at least 2 mm. Topush minimization efforts ASIC bonding pads were reduced to 100 μm by100 μm, but the 200 μm spacing between bonding pads and the ASIC itselfhad to be maintained to provide space for wirebonding. The attachmentpads for the PZT coupon was also shrunk and placed closer to the edge ofthe board, with the rationale that the PZT coupon did not have to whollysit on the board, but could hang off it. Additionally, the location ofthe pads relative to the ASIC was also modified to facilitate bonding.In the original design, the bond pad layout surrounding the ASICrequired two wirebonds to cross. This is not impossible, but verydifficult to avoid shorting the pads. Thus, the pad layout was shiftedso that the bonds are relatively straight paths. Finally, during animalexperiments, it was found that alignment of the implantable device wasquite difficult. To combat this, four 1 inch test leads that extendedoff the board were added, two of which connected directly to the sourceand drain of the device to harvest power could be measured and to usethat as an alignment metric. The other two leads connect to the gate andcenter ports in order to obtain a ground truth signal. In order toprevent confusion over which lead belonged to which port, the vias weregiven unique geometries. See FIG. 16A.

There was some fear that the test leads may be easily broken or wouldeasily displace the mote if force was applied on them. Thus, a versionwith serpentine traces was designed. Serpentine traces (FIG. 16B) haveoften been used to enable deformable interconnects, as their structureallows them to “accordion” out. Conceptually, the serpentine tracedesign can be through of a series of cantilevers in series via connectorbeams.

Along with the presented designs, a miniaturized version of theimplantable device using both sides of the substrate was also designedand assembled. In this design, the board measures roughly 1.5 mm by 0.6mm by 1 mm. Due to the miniaturization of the board, a 5 mil silver wire“tail” was attached to the device for recording. This version was nottested in vivo.

The ASIC and PZT coupon were attached to the PCB substrate usingadhesives. There are three majors concerns to choosing an adhesive: 1)the adhesive needs to fix the ASIC and PZT tightly enough that theultrasonic power from wirebonding does not shake the components, 2) dueto the sub-millimeter scales and pitches of the components/substratepads, application of the adhesive was done in a relatively precise way,and 3) the adhesive must be electrically conductive.

The ASIC and diced PZT were originally attached to the PCB substrateusing a low temperature-curing solder paste. Solder paste consists ofpowder metal solder suspended as spheres in flux. When heat is applied,the solder balls begin to melt and fuse together. However, it was foundthat the curing of the solder paste would often result in translating orrotating the PZT coupon or mote during reflow. This presented problemsfor PZT alignment and power harvesting, as well as problems forwirebonding due to the bondpads no longer being appropriately positionedfrom the chip. However, it was found that a two-part silver epoxy, whichsimply consists of silver particles suspended in epoxy was capable ofcuring without repositioning the chip or PZT coupon. Thus, the ASIC anddiced PZT were pasted onto the PCB using a two-part conductive silverepoxy (H20E, Epotek, Billerica, Mass.). The PCBs were then affixed to aglass slide using Kapton tape (Polyimide Film Tape 5413, 3M, St. Paul,Minn.) and put into a convection oven at 150° C. for 15 minutes to curethe epoxy. While higher temperatures could yield faster curing (FIG.17), care was taken to avoid heating the PZT beyond 160° C., half theCurie temperature of the PZT. Heating the PZT any higher runs the riskof depolarizing the PZT. It was found that the 150° C. cure had noeffect on the CMOS performance.

The connections between the top of the PZT and the PCB as well as theASIC and the PCB were made by wirebonding 1 mil Al wire using anultrasonic wedge bonder (740DB, West Bond, Scotts Valley, Calif.); inthis method of bonding, the Al wire is threaded through the wedge of thebondhead and ultrasonic energy “scrubs” the Al wire against thesubstrate, generating heat through friction. This heat results inwelding the two materials together.

Wirebonding to the ASIC was challenging to avoid shorts due to the sizeof the CMOS pads and the size of the foot of the wirebond. This problemwas accentuated due to the positioning of the wirebonding targets in thefirst version of the implantable device board, which forced the feet oftwo bonds to be placed across the smaller width of the ASIC pad ratherthan the length. While thinner gold wire was available to use forbonding, the difficulty of bonding gold thermosonically with a wedgebonder made it impractical to use gold wires for bonding with thisequipment. Furthermore, in order to effectively wirebond, it isimportant to have a flat and fixed substrate; hence, our original designof having the ASIC and PZT on different sides of the board often causedtrouble during the wirebonding process in our first version ofimplantable boards. Thus, the substrate design choices made in thesecond iteration of the implantable device (moving ASIC and PZT to thesame side, repositioning the pads to provide straight paths to wirebondtargets) greatly improved wirebonding yield.

Finally, because an ultrasonic bonder was used, it was found thatbonding to the PZT resulted in a charge build up would damage the chiponce the PZT was fully bonded to the substrate. To avoid this, thesource and drain test leads of the device were discharged to Earthground directly prior to wirebonding the PZT.

The final step of the implantable device assembly is encapsulation. Thisstep achieves two goals: 1) insulation of the PZT, bondpads, and ASICfrom aqueous environments and 2) protection of the wirebonds between theASIC/PZT coupon and the PCB. At the same time, there must be some methodto either remove or prevent the encapsulant from covering the recordingelectrodes. Additionally, the encapsulant must not impede deviceimplantation. Finally, while it is not crucial, it is of interest tochoose an encapsulant that is optically transparent so that the devicecan be inspected for physical defects if some damage occurred during theencapsulation.

The first encapsulant used was Crystalbond (509′, SPI Supplies, WestChester, Pa.). Crystalbond is an adhesive that is solid at roomtemperature but begins to soften′ at 71° C. and melts into a viscousliquid at 121° C. Upon removing heat from the Crystalbond, itre-solidifies within minutes, allowing for good control. To encapsulatethe implantable device, a small flake of Crystalbond was shaved off witha razor and placed directly over the device. The board was then heatedusing a hotplate, first bringing the temperature to around 70° C. whenthe flake would begin to deform and then slowly increasing thetemperature until the Crystalbond became fully liquid. Once the edge ofthe liquid Crystalbond drop expanded past the furthest wirebond but notthe recording pad, the hotplate was turned off and the board was quicklymoved off the plate onto a cooling chuck where the Crystalbond wouldre-solidify.

While Crystal bond was effective, it was found that UV curable epoxidecould give us better selectivity and biocompatibility, as well as rapidcuring. First, a light-curable acrylic (3526, Loctite, Dusseldorf;Germany) was tested, which cures with exposure to ultraviolet light. Asewing needle was used as an applicator to obtain high precision and theepoxy was cured with a 405 nm laser point for 2 minutes. This epoxyworked well, but was not medical-grade and thus not appropriate for abiological implant. Thus, a medical-grade UV curable epoxy (OG116-31,EPO-TEK, Billercia, Mass.) was tried. The epoxy was cured in a UVchamber (Flash, Asiga, Anaheim Hills, Calif.) with 92 mW/cm² at 365 nmfor 5 minutes. While this epoxy was slightly less viscous than theLoctite epoxy, using a sewing needle again as an applicator allowed forselective encapsulation. As an insulator and protection mechanism forthe wirebonds; the epoxy was very effective, but was found to leakduring prolonged submersion in water (˜1 hour). A second medical gradeepoxy which touted stability for up to a year, was considered (301-2,EPO-TEK, Billerica, Mass.), but was found to be not viscous enough andrequired oven-baking for curing. Despite the instability of the UVepoxy, the duration of use was suitable for acute in vivo experiments.

To improve encapsulant stability, parylene-C was. also considered as anencapsulation material. Parylene-C is an FDA approved biocompatiblepolymer which is chemically and biologically inert, a good barrier andelectrical insulator, and extremely conformal when vapor deposited).Vapor deposition of Parylene-C is achieved by vaporizing powderParylene-C dimer at temperatures above 150° C. The vapor Parylene-Cdimer is then heated at 690° C. in order for pyrolysis to occur,cleaving the Parylene-C dimer into monomers. The monomer then fills thechamber, which is kept at room temperature. The monomer almostinstantaneously polymerizes once it comes into contact with anysurfaces. For all devices, Paraylene-C was deposited using a parylenedeposition system (SCS Labcoter 2 Parylene Deposition System, SpecialtyCoating Systems, Indianapolis, Ind.) with the parameters shown inTable 1. Note that the table indicates the chamber gauge temperature as135° C. This is distinct from the actual chamber temperature; rather thechamber gauge is simply the vacuum gauge of the process chamber. It isimportant to keep the temperature to at least 135° C. to preventparylene from depositing onto the gauge. For the first batch of FR-4boards, parylene was addressed by selectivity by using Kapton tape tomask off the electrodes. However, it was found that due to the smallpitch between the recording electrodes and the ASIC wirebonding targets,there was not enough surface area for the tape to affix well to theboard and it often slipped off, resulting in coated electrode pads. Inthe second iteration of implantable device, a parylene coat wasattempted using a strategy in which the entire board was coated, thenremove the parylene off the electrodes with a probe tip. In order toassure that parylene was coated onto the entire device, the implantabledevices were suspended in air by damping them between two stacks ofglass slides.

TABLE 1 Parylene-C Deposition Parameters Furnace Temperature 690 deg. C.Chamber Gauge Temperature 135 deg. C. Vaporizer Temperature 175 deg. C.Base Pressure  14 mTorr Operating Pressure  35 mTorr Paralyene-C Mass  5g

The following provides additional details for manufacturing theimplantable device.

Before beginning to work with the PCBs, ASICs, or PZT coupons, preparetwo sample holders for the dust boards. To do so, simply take two glassslides (3 mm×1 mm×1 mm slides work well) and put a strip of double-sidedtape on the slide lengthwise. The tape will be used to fix the dustmotes in place so that the rest of the steps can be performed. On one ofthe slides, also add a piece of Kapton tape (3M) sticky-side up on topof the double-sided tape. This slide will be the slide used for curingas the high temperature of the cure can cause problems with the adhesiveon the double-sided tape.

Next, mix a small amount of silver paste by weighing out a 1:1 ratio ofpart A and part B in a weigh boat. A large amount of silver-epoxy is notneeded for the assembly process. Shown below is roughly 10 g of epoxy (5g of each part) which is more than enough for three boards, Note thatthe mixed-silver epoxy has a shelf life of two weeks if placed at 4° C.So leftover epoxy can and should be refrigerated when not in use.Additionally, older epoxies (several days to a week) tend to be slightlymore viscous than fresh epoxy which can make application easier.

The substrates come panelized and will need to be removed. Each board isconnected to the panel at several attachment points on the test leadsand vias—these attachment points can be cut using a micro-scalpel(Feather Safety Razor Co., Osaka, Japan). Once the PCB has beensingulated, using carbon-fiber tipped tweezers or ESD plastic tweezers,place the singulated PCB onto the high-temperature sample holder.

The diced/thinned die are shipped on dicing tape, which can make ittricky to remove the die. In order to reduce the adhesion between thedie and tape, it can be helpful to deform the tape. Using carbon-tippedor ESD plastic tweezers, gently press the tape and work the tweezers ina circular motion around the die. To check if the die has been freed,gently nudge the chip with the tip of the tweezers. If the die does notcome off easily, continue to press into tape surrounding the chip. Oncethe chip has come off, carefully place the chip onto thehigh-temperature sample holder next to its board. It is advisable tobring the sample holder to the chip rather than the other way around sothat the chip is not in transit, Care must be taken in this step toavoid losing or damaging the die. Never force a die off the tape, asexcessive force can cause a chip to fly off the tape.

Next, attach the die using silver epoxy. Under a microscope, use a pinor something equally fine to apply a small amount silver epoxy to theCMOS pad on the PCB. In this step, it is better to err on the side oftoo little epoxy than too much epoxy since more silver paste can alwaysbe applied, but removing silver paste is non-trivial. Small amounts ofuncured epoxy can be scraped away with the same tool used forapplication, just ensure the epoxy has been wiped off the tool.

Once the epoxy has been placed on the pad, the ASIC can be placed ontothe epoxy. Due to a CAD error, some of the chips have been reflected. Itis important to take care that chips which are reflected have beenoriented the correct way on the board to ensure no wires need to crossduring wirebonding.

Once the ASICs have been situated on the boards correctly, the silverepoxy can be cured by placing it into an oven at 150° C. for 15 minutes.Note that different temperatures can be used if needed. See FIG. 17 fordetails. After the silver epoxy has been cured, double-check adhesion bygently pushing on each die, If the die moves; a second coat of silverepoxy will be needed.

To prepare for wirebonding, move the devices from the high-temperaturesample holder to the regular sample holder. This change is necessarybecause the adhesion of double-sided tape is stronger than that of theKapton tape so wirebonding will be made easier. A piece of double-sidedtape should be good enough to affix the sample holder to thewirebonder's workholder. It is best to ensure that the workholder hasnot been previously covered with double-sided tape so that the testleads do not get accidentally stuck to anything. If necessary,clean-room tape can be used to provide additional clamping of the sampleholder.

Ensure the wirebonder is in good condition by making bonds on theprovided test-substrate using default settings. Ensuring that thewirebonder is in condition is important, as a damaged wedge will notbond well and effectively just damage the ASIC pads. Forward bonds(first bond on the die, second bond on the substrate) should be made inthe following order: 1. Gate. 2. Bulk. 3. Center. 4. Drain. 5. Source.While it is not critical that the bonds be made in this order, thisorder minimizes the number of substrate reorientations and preventsaccidental damage to the bonds due to the bondhead. Small angleadjustments of the workholder can be made to facilitate bonding; it isimperative that this bond be as straight as possible. In the case thatthe foot of the second bond lifts from the substrate, changing thenumber of bonds to one and bonding the foot again may help. If properadhesion cannot be made, a potential solution is to connect the foot ofthe bond and the substrate using silver epoxy. Additionally, shortscaused by two bond-feet touching can be resolved by very carefullycutting away the bridging metal using a microscalpel.

Known working bonding parameters can be found in Table 2, below. Theseparameters are simply guidelines and should be modified as necessary.Needing excess power (greater than 490) is typically indicative of aproblem: substrate fixing (both PCB to glass slide and CMOS to PCB),wedge condition, and pad condition should all be checked. In the case ofpad condition, damaged pads due to previous wirebonding attempts willusually require higher power—in some cases, the devices are salvageable,but failed attempts to bond with power higher than 600 usually resultsin too much damage to the pads for good bonding.

TABLE 2 Westbond 7400B A1 Parameters for ASIC Bond # Power Time 1 (ASIC)420 40 ms 2 (Substrate) 420 40 ms

Post-wire bonding, the device should undergo electrical testing toensure proper bonding. If using a type 1 die, the I-V characteristicsshould be roughly as shown in Table 3.

TABLE 3 Typical I-V characteristics for Type 1 Die under V_(ds) = 0.1 VV_(gs) I_(ds)   0 V  0.5 μA 0.1 V  0.74 μA 0.2 V  10.6 μA 0.3 V  51.4 μA0.4 V 0.192 mA 0.5 V  0.39 mA 0.6 V  1.14 mA 0.7 V  1.55 mA 0.8 V  1.85mA

If the I-V characteristics do not seem correct, a valuabletroubleshooting method is checking the resistances between the drain andcenter, source and center, and drain and source. If the die is workingproperly, one should expect roughly 90 kΩ resistance between the drainand center and source and center, and roughly 180 k Ω between the drainand source.

After confirmation that the FET is connected properly, the PZT couponshould be attached. This is done in a similar fashion to attaching theASIC: place a dab of silver epoxy using a sewing needle on theappropriate pad. It is best to put the epoxy dab on the back edge of thepad (towards the end of the board) since the PZT coupon will not becentered on the pad, but pushed back so that the coupon hangs off theboard. Keep in mind that the polarity of the PZT coupon has a smalleffect on its efficiency. To determine whether or not the coupon is inthe correct position, check if the bottom face is larger than the topface. Due to the path of the dicing saw, the bottom of the coupon, isslightly larger than the top of the coupon. Thus, the edges of thebottom face can be seen from a top down view, then the coupon has beenplaced in the same orientation as it was when the disk was diced.

Wirebonding the PZT is done in a similar manner to the ASIC (forwardbonding, the PZT to the PCB). However, one crucial change is that thedrain and source vias should be grounded. There is an earth ground portnext to Westbond which can be accessed via a banana connector. As aguideline, the parameters shown in Table 4 have been known to work.

TABLE 4 Westbond 7400B A1 Parameters for PZT Bond # Power Time 1 (PZT)390 40 ms 2 (Substrate) 490 40 ms

A successful bond may require several attempts depending on how well thePZT coupon is attached to the substrate. The more attempts that aremade, the worse the mechanical structure of the PZT becomes (the silvercoating will become damaged) so it is best to try to very quicklyoptimize the process. Bonds that fail due to foot detachment generallyimply not enough power. Bonds that fail due to the wire breaking at thefoot generally imply too much power.

After a successful bond is made, it is always good to do anotherelectrical test to ensure that bonding the PZT has not damaged the ASIC.

As a final step, test wires were soldered to the vias and encapsulatethe device, The test wires are 3 mil silver wires. Nate that these wiresare insulated: the insulation can be removed by putting the wire closeto a flame (not in the flame) and watching the plastic melt and recede.

After soldering wires, the device can now be encapsulated. Theencapsulant is OG116-31 medical-grade UV curable epoxy and should bedispensed using a sewing needle. An effective method is to put a largedrop of epoxy over the PZT coupon and a large drop over the ASIC. Usinga clean needle, push the droplet over the board so that the entiretopside of the board is coated. The epoxy should wet the board, but notspill over due to its surface tension. Once the main body of the boardis coated, the vias should also be coated, as well as the side faces ofthe piezo. The board can then be cured in a UV chamber for roughly 5minutes. It has been found that the test wires can occasionally contactsomething in the UV chamber and short the ASIC. Thus, prior to puttingthe board in the chamber, it is good to wrap the wires down or place iton some tape in order to isolate them from any chamber surfaces.

Following curing, the backside should be coated. In particular theexposed PZT coupon which hangs over the board as well as the backside ofthe test vias and the two vias on the backside of the board whichconnect the electrodes to the topside of the board. This part can be alittle tricky due to the small space between the backside vias and theelectrodes, so it is best to start with a very small amount of epoxy andplace it near the edge of the board, then drag the epoxy up towards thevias. The backside of the board should be cured in the same manner asthe topside. Once the board is fully encapsulated, a final electricaltest should be done, and upon passing, the implantable device is nowcomplete.

Example 2—Set-Up for Testing Implantable Devices

Testing of implantable has always been tricky due to the thinness of thetest leads that extend out from the board. Clipping onto and off ofthese vias for I-V measurements has often resulted in pulling the leadsoff the body of the device. Furthermore, due to the test leads, it isdifficult to perform water-tank test measurements; as exposedelectronics in water would result in shorts. In order to circumvent thisissue, a PCB was designed to serve as a testbed for implantable devicemeasurements. The PCB (Bay Area Circuits, Fremont, Calif.) was made ofFR-4 and 60 mil thick; it includes four vias, distributed on the boardto match the layout of the version two implantable device boards.

Gold header pins (Pin Strip Header, 3M, Austin, Tex.) were soldered intothe vias so that they extended from the board on both sides of theboard. This enabled us to place our devices onto the test bed, and tapinto the implantable by accessing the header pins. Next, to insulate thevias, plastic caps made out of polyethylene terephthalate (PETG) were 3Dprinted (Flashforge Creator X, FlashForge, Jinhua, China). These capswere printed with a groove so that an O-ring could be placed inside thegroove and create a waterproof seal around the header pins. The capswere connected to the board and compression was created by drilling 2 mmholes through the PCB and cap using a micro-mill (47158, Harbor Freight,Camarillo, Calif.) and screwing the cap and board together. Wiresextending from the testbed were soldered to the header pins and the pinswere then encapsulated. To measure the effectiveness of the seal, theboards were submerged in an aqueous 6 M NaCl solution and the resistancebetween the pins was measured using a Keithley 2400. A MATLAB script waswritten to automatically record and plot the resistance over time. Adrop in the resistance would indicate that the seal was broken. As anadditional test, a piece of litmus paper was also put under the plasticcap with the intention that if the cap leaked, the litmus paper wouldchange color. The pins were encapsulated using the same medical gradeepoxy used to encapsulate the implantable device boards, and parylenewas deposited over the epoxy on the back side of the testboards for acompletely waterproof barrier. The resistance between the twoneighboring pins of the testbed submerged in salt water solution as afunction of time for only epoxy insulation and epoxy plus paryleneinsulation was measured. Without a parylene barrier, the epoxy began toleak, allowing salt water to short out the pins of the testbed.

Example 3—Implantable Devices Encapsulated in Silicon Carbide

Rather than an epoxy encapsulant, silicon carbide (SiC) may be a moreeffective material for insulating and protecting the implantable device.SiC is formed by the covalent bonding of Si and C, forming tetrahedrallyoriented molecules with short bond length and thus, high bond strength,imparting high chemical and mechanical stability. Amorphous SiC (a-SiC)has been welcomed by the biomedical community as a coating material asit can be deposited at much lower temperatures than ordinarily requiredby crystalline SiC and is an electrical insulator. Deposition of a-SiCis generally performed via plasma enhanced chemical vapor deposition(PECVD) or sputtering. Ongoing research using sputtered a-SiC has shownthat it is difficult to achieve a pinhole free layer of SiC. Rather,PECVD using SiH₄ and CH₄ as precursors is capable of yieldingimpressive, pinhole free SiC films.

Furthermore, implanted a-SiC has shown impressive biocompatibility.Previous studies have shown that a 50 μm iridium shaft coated with a-SiCimplanted in the rabbit cortex for ˜20 days did not show the usualchronic inflammatory response of macrophage, lymphocyte, monocyterecruited to the insertion site. See Hess et al., PECVD silicon carbideas a thin film packaging material for microfabricated neural electrodes,Materials Research Society Symposium Proceedings, vol. 1009, doi:10.1557/PROC-1009-U04-03 (2007).

It is interesting to consider an approach to implantable devices thatwould involve constructing the devices on silicon with a silicon carbideencapsulant for a truly chronic implant. A possible process is shown inFIG. 18. One of the largest challenges here is ensuring that the PECVDof SiC dues not depole the piezoelectric material. In order to havecontamination-free films, it is important to deposit at a minimumtemperature of 200° C., but below the Curie temperature of thepiezoelectric transducer.

Example 4—Power Transfer to and Backscatter of a Miniaturized UltrasonicTransducer

A set of experiments were carried out with PZT due to the relative easeof obtaining PZT crystals with varying geometry. Metalized PZT sheets ofseveral thicknesses were obtained (PSI-5A4E, Piezo Systems, Woburn,Mass. and PZT 84, APC Internationals, Mackeyville, Pa.), with a minimumPZT thickness of 127 μm. The PZT was fully encapsulated in PDMS siliconfor biocompatibility.

The most commonly used method to dice PZT ceramics is to use a waferdicing saw with an appropriate ceramic blade to cut PZT sheets intoindividual PZT crystals. The minimum resolution of the cut is determinedby the kerf of the blade and can be as small as 30 μm.

Another possible option is to use a laser cutter. Unlike the dicing saw,laser cutting realizes the cuts by focusing a high-power laser beam ontoa material, which melts, vaporizes, removes, and scribes the piece. Theprecision of laser cutting can be down to 10 μm and is limited by thewavelength of the laser. However, for treating sensitive samples such asPZT ceramics, the temperature at the site of cuts can be damaging to thepiezoelectric performance of the material. Excimer laser cutting ofceramics uses UV laser to cut with excimer from noble gases, but suchlaser cutter is extremely expensive and no suitable services arecurrently available. As a result, a dicing saw was used to perform allthe cuts.

In order to drive or extract electrical energy from the PZT, anelectrical connection is made to both the top and bottom plates. Thematerials typically used as an electrode for PZT are silver or nickel.Silver is generally used for a wide variety of non-magnetic and ACapplications and silver in the form of flakes suspended in a glass fritis usually screened onto the ceramic and fired. For high electric fieldDC applications, silver is likely to migrate and bridge the two plates.As a result, nickel, which has good corrosion resistance and does notelectro-migrate as readily can be electroplated or vacuum deposited asan alternative.

Both materials can be soldered onto with the appropriate solder andflux. For instance, silver is soluble in tin, but a silver loaded soldercan be used to prevent scavenging of silver in the electrode. Phosphorcontent from the nickel plating can make soldering tricky, but thecorrect flux can remove surface oxidation. However, when soldering, inorder to avoid exceeding the Curie point and depoling the PZT sample,the soldering temperature must be between 240 and 300° C. Even at thesetemperatures, since the PZT is also pyroelectric, one must be carefulnot to exceed 2-4 seconds of soldering time.

Alternatively, an electrical connection can be made using either silverepoxy or low temperature soldering using solder paste. Standard two-partsilver epoxy can provide a sufficient electrical conductivity and can becured even at room temperature overnight. However, the joints tend to befragile and can easily break during testing. The bond can be reinforcedby using a non-conductive epoxy as an encapsulation but this additionallayer presents a mechanical load to the PZT and can significantly dampenits quality factor. Low-temperature solder paste on the other handundergoes a phase change between the temperature of 150 and 180° C. andcan provide great electrical connection and a bond strength that iscomparable to that achieved with flash soldering. Therefore, thelow-temperature soldering approach was used.

Wafer dicing is capable of cutting PZTs into small crystals of 10's ofμm. However, samples that are smaller than 1 mm in dimension areextremely difficult to handle with tweezers and bond to. In addition,due to the variation in the length of wire used to interface with topand bottom plates of PZT crystals (and therefore parasitic inductanceand capacitance introduced by the wire) and the amount of solder pastedispensed across a number of samples, the impedance spectroscopemeasurements were inconsistent.

Therefore, a 31 mil thick two-layer FR-4 PCB where all of the electricalinterconnects short and de-embed out the parasitics from the wires andthe board was fabricated. The fabricated board, which includes numeroustest structures and a module for individually characterizing 127 μm, 200μm, and 250 μm thick PZT crystals are shown with dimensions in FIG. 19.Each unit cell in the test module contains two pads with specifieddimensions on one side of the PCB to interface with the PZT crystals andpads for discrete components for backscattering communication on theopposite side. The pitch between the unit cells is limited by the sizeof the discrete components and is roughly 2.3 mm×2 mm.

In order to avoid directly handling tiny PZT crystals, FIGS. 20A-Eoutline a scalable process flow to bond PZT onto the PCB. As shown inFIG. 20A, the solder paste is dispensed using a pump at a constantpressure and for a controlled amount of time on one of the pads on thetop side. The pads are either 250 μm², 200 μm², or 127 μm² based on thethickness of the PZT used. FIG. 20B shows a PZT piece larger than thepad (that can be easily handled) is placed on top to cover the pads. Theboard and piezo assembly are baked in an oven to cure the solder paste.Therefore, PZT crystals are now bonded to pre-soldered bumpedelectrodes. FIG. 20C shows a wafer dicing saw makes a total of four cutsalong the edges of the pad with the solder paste using alignment markerson the board, with non-bonded areas dropping off and leaving an array ofsmall PZT crystals bonded to the PCB. FIG. 20D shows single wirebondmakes an electrical contact between the top plate of the PZT and anelectrode on the PCB, completing the circuit. Finally, FIG. 20E showsthe entire assembly is encapsulated in PDMS (Sylgard 184, Dow Corning,Midland, Mich.) to protect the wirebond and provide insulation.

Since piezoelectric material is an electro-mechanical structure, itselectrical and mechanical properties were characterized. The followingdetails the test setup and techniques to perform such measurements.

Any electrical device can be modeled as a black box using a mathematicalconstruct called two-port network parameters. The properties of thecircuits are specified by a matrix of numbers and the response of thedevice to signals applied to its input can be calculated easily withoutsolving for all the internal voltages and currents in the network. Thereare several different types of two-port network parameters, such asZ-parameters, Y-parameters, S-parameters, and ABCD-parameters, etc. andthe conversion between different parameters can be easily derived. Theapparatus that enables us to extract these parameters is called a vectornetwork analyzer (VNA). A VNA incorporates directional couplers todecompose the voltage in each port into incident and reflected waves(based on impedance mismatching), and calculate the ratio between thesewaves to compute scattering or S-parameters.

Before performing measurements using a VNA, one must calibrate theinstrument since the internal directional couples are non-ideal.Calibration also allows us to move the reference plane of themeasurement to the tips of the cable, i.e., calibrate out parasiticsfrom the cable. There are several calibration standards but the mostcommonly used is open, short, and load calibration procedures. Themeasurement schematic is shown in FIG. 21. Alligator clips, which aresoldered onto the ends of the coaxial cable, are used to interface withthe top/bottom plates. The parasitics from the clips were notsignificant below 100 MHz.

As an example, a VNA (E5071C ENA, Agilent Technologies, Santa Clara,Calif.) was used to measure the electrical properties of a (250 μm)³ PZTcrystal. It was noted that the measured capacitance of the PZT crystalvastly differs from the capacitance expected from a simpleparallel-plate capacitance model due to significant parasiticcapacitances from the PCB and the fixture (clip and connector). Sincethe VNA coefficients from the calibration step previously outlined onlymoved the measurement plane to the tips of the cable, open/short/loadcalibration structures fabricated on the same board were used to includethe board and fixture parasitics. The measured PZT response matched theexpected response after calibration.

Using this calibration technique, the impedance of the PZT can beplotted as a function of frequency, as shown in FIG. 22B. From thisplot, however, it is extremely difficult to determine whether there isany electro-mechanical resonance. When the simulation result with airbacking (no mechanical clamping) was overlaid, it was noticed that theimpedance spectroscopy matches well with the measurement at low and highfrequencies, with the exception of noticeable peak at resonant frequencyof roughly 6 MHz and its harmonics. Upon clamping and loading one sideof PZT with PCB (FR-4), it was seen that a significant dampening of theresonant peaks from air backing. Despite a lack of observable resonancein the measurement, a small blimp around 6 MHz was observed, and themechanical quality factor Q_(m) can be calculated using the followingequations,

$Q_{m} = \frac{f_{a}^{2}}{2Z_{r}{C_{p}\left( {f_{a}^{2} - f_{r}^{2}} \right)}}$

where f_(a) and f_(r) represent anti-resonant (where impedance ismaximized) and resonant frequency (where impedance is minimized), Z_(r)represents an impedance at resonance, and C_(p) is the low-frequencycapacitance. The calculated quality factor from the measurement isroughly 4.2 compared to 5.1 in simulation. According to the datasheet,the unloaded Q of the PZT is ˜500, indicating that FR-4 backing andwire-bonds are causing significant degradation of the quality factor.Despite the drastic reduction in the mechanical Q of the PZT crystals,experiments showed that the backscattered signal level only decreased byroughly ˜19.

In the electrical characterization setup, the VNA has a built-in signalgenerator to provide the input necessary for characterization. In orderto perform acoustic characterization of PZT, acoustic waves weregenerated and launched onto the sample to use as an input. This can beachieved with commercially available broadband ultrasonic transducers.

FIG. 23 shows the composition of a representative transducer, whichconsists of a piezoelectric active element, backing, and wear plate. Thebacking is usually made from a material with high attenuation and highdensity to control the vibration of the transducer by absorbing theenergy radiating from the back face of the active element while the wearplate is used to protect the transducer element from the testingenvironment and to serve as a matching layer.

Ultrasonic power transfer tests were performed using the home-builtsetup shown in FIG. 24. A 5 MHz or 10 MHz single element transducer (6.3mm and 6.3 mm active area, respectively, ˜30 mm focal distance, Olympus,Waltham, Mass.) was mounted on a computer-controlled 2-axis translatingstage (VelMex, Bloomfield, N.Y.). The transducer output was calibratedusing a hybrid capsule hydrophone (HGL-0400, Onda, Sunnyvale, Calif.).Assembly prototypes were placed in a water container such thattransducers could be immersed in the water at a distance ofapproximately 3 cm directly above the prototypes. A programmable pulsegenerator (33522B, Agilent Technologies Santa Clara, Calif.) and radiofrequency amplifier (A150, ENI, Rochester, N.Y.) were used to drivetransducers at specified frequencies with sinusoidal pulse trains of10-cycles and a pulse-repetition frequency (PRF) of 1 kHz. The receivedsignals were amplified with a radio frequency amplifier(BT00500-AlphaS-CW, Tomco, Stepney, Australia), connected to anoscilloscope (TDS3014B, Tektronix, Beaverton Oreg.) to collectultrasound signal and record them using MATLAB.

FIG. 25A and FIG. 25B show a representative measurement of the outputpower of the 5 MHz transducer as a function of the distance between thesurface of the transducer and the hydrophone (z-axis). The peak pressurein water was obtained at ˜33 mm away from the transducer's surface (FIG.25A), while the de-rated peak (with 0.3 dB/cm/MHz) was at ˜29 mm (FIG.25B). FIG. 26A shows the de-rated XZ scan of the transducer output,which show both near-field and far-field beam patterns and a Rayleighdistance or a focal point at ˜29 mm, matching the de-rated peak in FIG.25B. FIG. 26B shows a XY cross-sectional scan of the beam at the focalpoint of ˜29 mm, where the 6 dB beamwidth measured roughly 2.2 mm.

The total integrated acoustic output power of the transducer at variousfrequencies over the 6 dB bandwidth of the beam was nominally kept at aspatial-peak temporal-average ISPTA of 29.2 μW/cm², resulting in a totaloutput power of ˜1 μW at the focal point, with a peak rarefactionpressure of 25 kPa and a mechanical index (MI) of 0.005. Both thede-rated ISPTA and MI were far below the FDA regulation limit of 720mW/cm² and 1.9, respectively (FDA 2008).

FIG. 22A shows the measured power delivery efficiency of the fullyassembled prototype with cable loss calibrated out for various neuraldust node sizes as compared to analytical predictions made for this samesetup. Measured results matched the simulated model behavior veryclosely across all transducer sizes, with the exception of a few smallertransducer dimensions, likely due to the sensitivity to transducerposition and the ultrasound beamwidth. The measured efficiency of thelink for the smallest PZT crystal (127 μm)³ was 2.064×10⁻⁵, whichresulted in 20.64 pW received at the transducer nominally. A maximum of0.51 μW can be recovered at the transducer if the transmit output powerdensity was kept at 720 mW/cm². Such low power level harvested by thePZT is mainly due to the extreme inefficiency of broadband transducersthat were used for the experiments; dedicated, custom-made transducersat each transducer dimension with optimal electrical input impedancecould result in more than 2 orders of magnitude improvement in theharvested power level as predicted by the simulation model.

The frequency response of electrical voltage harvested on a (250 μm)³PZT crystal is shown in FIG. 22C. The resonant frequency was measured tobe at 6.1 MHz, which matches the shift in the resonant frequencypredicted for a cube due to Poisson's ratio and the associated modecoupling between resonant modes along each of the three axes of thecube. Furthermore, the calculated Q of 4 matched the electricallymeasured Q of the PZT.

The experimental result indicate that the analytical model for powercoupling to very small PZT nodes using ultrasound is accurate down to atleast ˜100 μm scale and likely lower. It remains to be seen just howmall a transducer can be fabricated before loss of function. Note thatmeasurements of even smaller nodes (<127 μm) were limited not by theprototype assembly process but by commercial availability of PZTsubstrates. Moving forward, the considerable volume of research andtechniques that has gone into micro- and nanoelectromechanical RFresonators was be used (see Sadek et al., Wiring nanoscale biosensorswith piezoelectric nanomechanical resonators, Nano Lett., vol. 10, pp.1769-1773 (2010); Lin et al., Low phase noise array-compositemicromechanical wine-glass disk oscillator, IEEE Elec. Dev. Meeting, pp.1-4 (2005)) and thin-film piezoelectric transducer (seeTrolier-McKinstry et al., Thin film piezoelectrics for MEMS, J.Electroceram., vol. 12, pp. 7-17 (2004)) to facilitate extremely small(10's of μm) transducers and to truly assess the scaling theory.

Example 5—Beamforming Using Interrogator Ultrasonic Transducer Array

In this example, an ultrasonic beamforming system capable ofinterrogating individual implantable sensors via backscatter in adistributed, ultrasound-based recording platform is presented. A customASIC drives a 7×2 PZT transducer array with 3 cycles of 32V square wavewith a specific programmable time delay to focus the beam at the 800μ mneural dust mote placed 50 mm away. The measured acoustic-to-electricalconversion efficiency of the receive mote in water is 0.12% and theoverall system delivers 26.3% of the power from the 1.8V power supply tothe transducer drive output, consumes 0.75 μJ in each transmit phase,and has a 0.5% change in the backscatter per volt applied to the inputof the backscatter circuit. Further miniaturization of both the transmitarray and the receive mote can pave the way for a wearable, chronicsensing and neuromodulation system.

In this highly distributed and asymmetric system, where the number ofimplanted devices outnumbers the interrogating transceivers by an orderof magnitude, beamforming can be used to efficiently interrogate amultitude of implantable devices. Research into beamforming algorithms,trade-offs, and performance in the implantable device platform hasdemonstrated that cooperation between different interrogators is usefulfor achieving sufficient interference suppression from nearbyimplantable devices. See Bertrand et al., Beamforming approaches foruntethered ultrasonic neural dust motes for cortical recording: asimulation study, IEEE EMBC, 2014, pp. 2625-2628 (August 2014). Thisexample demonstrates a hardware implementation of an ultrasonicbeamforming system for the interrogator and implantable device systemshown in FIG. 2A. The ASIC (see, e.g., Tang et al., Integratedultrasonic system for measuring body-fat composition, 2015 IEEEInternational Solid-State Circuits Conference—(ISSCC) Digest ofTechnical Papers, San Francisco, Calif., 2015, pp. 1-3 (February 2015);Tang et al., Miniaturizing Ultrasonic System for Portable Health Careand Fitness, IEEE Transactions on Biomedical Circuits and Systems, vol.9, no. 6, pp. 767-776 (December 2015)), has 7 identical channels, eachwith 6 bits of delay control with 5 ns resolution for transmitbeam-forming, and integrates high-voltage level shifters and areceive/transmit switch that isolates any electrical feed-through.

The ASIC operates with a single 1.8V supply and generates a 32V squarewave to actuate piezoelectric transducers using integrated charge pumpsand level shifters. The system delivers ˜32.5% of the power from the1.8V supply to the 32V output voltage and ˜81% from 32V to the outputload (each transducer element is 4.6 pF). The ASIC block diagram isshown in FIG. 2A; the circuit details to enable such low energyconsumption per measurement can be found in Tang et al., Integratedultrasonic system for measuring body-fat composition, 2015 IEEEInternational Solid-State Circuits Conference—(ISSCC) Digest ofTechnical Papers, San Francisco, Calif., 2015, pp. 1-3 (February 2015).The ASIC is fabricated in 0.18 μm CMOS with high voltage transistors.The chip area is 2.0 mm² and includes the complete system except for thedigital controller, ADCs, and two off-chip blocking capacitors.

The design of a transducer array is a strong function of the desiredpenetration depth, aperture size, and element size. Quantitatively, theRayleigh distance, R, of the array can be computed as follows:

$R = \frac{D^{2}}{4\lambda}$

where D is the size of the aperture and λ is the wavelength ofultrasound in the propagation medium. By definition, Rayleigh distanceis the distance at which the beam radiated by the array is fully formed;in other words, the pressure field converges to a natural focus at theRayleigh distance and in order to maximize the received power, it ispreferable to place the receiver at one Rayleigh distance where beamspreading is the minimum.

The frequency of operation is optimized to the size of the element. Apreliminary study in a water tank has shown that the maximum energyefficiency is achieved with a (800 μm)³ PZT crystal, which has aresonant frequency of 1.6 MHz post-encapsulation, resulting in λ ˜950μm. The pitch between each element is chosen to be an odd multiple ofhalf wavelength in order to beamform effectively. As a result, for thisdemonstration of beamforming capabilities, the overall aperture is ˜14mm, resulting in the Rayleigh distance of 50 mm. At 50 mm, given theelement size of 800 μm, each element is sufficiently far from the field(R=0.17 mm); therefore, the beam pattern of an individual element shouldbe omni-directional enough to allow beamforming.

There are several transmit and receive beamforming techniques that canbe implemented. In this example, time delay-and-sum transmit beamformingalgorithm is chosen, such that the signals constructively interfere inthe target direction. This algorithm is capable of demonstratingbeam-steering and maximal power transfer to various implantable devices.In order to accommodate backscatter communication to multipleimplantable devices simultaneously, more sophisticated algorithms may berequired. These can include delay-and-sum beamforming, linearlyconstrained minimum-variance beamforming, convex-optimized beamformingfor a single beam, ‘multicast’ beamforming w/convex optimization,maximum kurtosis beamforming, minimum variance distortionless responserobust adaptive beamforming, polyadic tensor decomposition, anddeconvolution of mote impulse response from multi-Rx-channel time-domaindata. The detailed treatment of one aspect of this problem is describedin Bertrand et al., Beamforming approaches for untethered ultrasonicneural dust motes for cortical recording: a simulation study, IEEE EMBC,2014, pp. 2625-2628 (August 2014).

Each of the 7 channels is driven by 3 cycles of 32V square wave with aspecific programmable time delay such that the energy is focused at theobservation distance of 50 mm. The time delay applied to each channel iscalculated based on the difference in the propagation distance to thefocus point from the center of the array and the propagation speed ofthe ultrasound wave in the medium.

Ultrasim was used to characterize the propagation behavior of ultrasoundwave in water with the 1D array described above. Simulated XY (FIG. 27A)and XZ (FIG. 27B) cross-sectional beam patterns closely match themeasurement as shown, despite not modeling the PDMS encapsulation.

Water is used as the medium for measuring the beamforming system as itexhibits similar acoustic properties as the tissue. Pre-metalized LeadZirconate Titanate (PZT) sheets (APC International, Mackeyville, Pa.)are diced with a wafer saw to 800 μm×800 μm×800 μm crystals (parallelcapacitance of 4.6 pF each), which is the size of each transmit element.Each PZT element is electrically connected to the corresponding channelin the ASIC by using a conductive copper foil and epoxy for the bottomterminal and a wirebond for the top terminal. The array is encapsulatedin PDMS (Sylgard 184, Dow Corning, Midland, Mich.) to protect thewirebond and provide insulation. The quality factor of the PZT crystalpost encapsulation is ˜7. The array is organized into 7 groups of 2×1elements, with the pitch of ˜5/2λ˜2.3 mm. The array measuresapproximately 14 mm×3 mm. Finally, the entire assembly is encased in acylindrical tube with the diameter of 25 mm and the height of 60 mm andthe tube is filled with water.

The transducer array's 2D beam pattern and output are calibrated using acapsule hydrophone (HGL-0400, Onda, Sunnyvale, Calif.). The hydrophoneis mounted on a computer-controlled 2D translating stage (VelMex,Bloomfield, N.Y.). The hydrophone has an acceptance angle (−6 dB at 5MHz) of 30°, which is sufficient to capture the beam given thetransmission distance of 50 mm and the scan range (±4 mm).

The measured XY cross-sectional beam pattern with the overlay of thearray is shown in FIG. 27A. The applied delay for each transducer in thearray (element) is shown in FIG. 27B. The −6 dB beamwidth at the focalpoint is 3.2 mm 3λ. The flexibility of the ASIC allows for both wide andgranular programming of the delays. The peak pressure level of the arrayat 50 mm before and after beamforming is −6 kPa and −20 kPa,respectively. The 3× in the transmitted output pressure wave afterbeamforming matches the simulation. The simulation also verifies thatthe Rayleigh distance of the array is at 50 mm as shown in FIG. 27C.

Additionally, in order to verify the capability to interrogate multipleimplantable devices, it was verified the beam steering capability of thearray as shown in FIG. 28A (showing beam steering at three differentpositions in the XY-plane), with the time delay for each beam positionshown underneath in FIG. 28B. The 1D beam steering matches very closelywith the simulation, as shown in FIG. 28C. Note that the beam steeringrange is limited to ±4 mm due to the mechanical construct of the array,rather than the electronic capability.

The hydrophone is replaced with an implantable device (with a 800 μm×800μm×800 μm bulk piezoelectric transducer) and placed at the transmissiondistance of 50 mm to verify the power link. The open-circuitpeak-to-peak voltage measured at the mote is 65 mV, for a transmitpulse-duration of 2.56 μs. The spatial peak average acoustic powerintegrated over the −6 dB beamwidth at the focal point is 750 μW, whichis 0.005% of the FDA safety limit. The maximum harvestable power at themote is 0.9 μW, resulting in the measured acoustic-to-electricalconversion efficiency of 0.12%. The measured result is in agreement withthe link model (see Seo et al., Model validation of untetheredultrasonic neural dust motes for cortical recording, J. Neurosci.Methods, vol. 244, pp. 114-122 (2015)). The system delivers 26.3% of thepower from the 1.8V power supply to the transducer drive output (definedas driving efficiency) and consumes 0.75 μJ in each transmit phase.

The ultrasonic backscatter communication capability of the system isverified by measuring the difference in the backscattered voltage levelas the input to the backscatter circuit (see Seo et al., Modelvalidation of untethered ultrasonic neural dust motes for corticalrecording, J. Neurosci. Methods, vol. 244, pp. 114-122 (2015)), and isadjusted with a DC power supply. The transmit time and the period of thesystem are 3 μs and 80 μs, leaving a ˜77 μs window for reception. A 2×1element in the center of the array is used for receiving thebackscatter. The output of the receive crystals is amplified anddigitized for processing. The measured backscatter sensitivity is ˜0.5%per volt applied to the input of the backscatter circuit, which is inagreement with the simulation. The overall performance of the system issummarized in Table 4.

TABLE 4 Summary of System Performance Supply voltage 1.8 V Outputvoltage 32 V Number of channels 7 Operating frequency 1.6 MHz Chargepump + level 26.3% shifter efficiency Acoustic-to-Electrical 0.12%efficiency Backscatter change 0.5%/V Energy per transmit 0.75 μJ phase

Our measurements with the ultrasonic beamforming system suggest thattransmit beamforming alone can provide sufficient signal-to-noise ratio(SNR) to enable multiple sensors interrogation in the neural dustplatform. The decrease in the SNR with the miniaturization of the dustmote can be largely mitigated by implementing receive beamform.Furthermore, in order to increase the rate of interrogation, one couldexplore an alternative means of multiplexing, such as spatialmultiplexing where multiple motes are interrogated simultaneously withthe same transmit beam. However, it is important to consider the systemdesign tradeoff between processing/communication burden to powerconsumption. Additionally, sufficient suppression of interferences fromnearby dust motes is necessary to achieve the required SNR.

The acoustic-to-electrical efficiency at 0.12% currently dominates theefficiency

$\left( \frac{P_{harvested}}{P_{1.8\mspace{11mu} V\mspace{11mu} {supply}}} \right)$

of the overall system. Despite such low efficiency of the power link, if˜1% of the FDA safety regulation (spatial peak average of 1.9 W/cm²) canbe outputted, it is possible harvest up to 0.92V peak-to-peak voltageand 180 μW at the 800 μm ultrasonic transducer 50 mm away in water.

Furthermore, the low efficiency of the power link in this demonstrationis attributed to such large transmission distance, as determined by thearray aperture and the element size. For peripheral nerve intervention,for example, the desired transmission distance is approximately 5 mm,which includes the thickness of skin, tissue, etc. In order to be at thefar field of the array, the aperture should be ˜4.4 mm. Further scalingof each element can reduce the overall dimensions of the array apertureand the transmission distance down to the desired 5 mm. Simulationindicates that acoustic-to-electrical efficiency up to 1% can beachieved in water with a 100 μm receive ultrasonic transducer.

For transmission in tissue, assuming 3 dB/cm/MHz loss in tissue, FIG. 29shows the scaling of both link efficiency and received power level givenoperation at 1% of the FDA safety limit. Despite this ratherconservative loss, at 100 μm, the simulation indicates that it ispossible to harvest up to 0.6V peak-to-peak voltage and 75 μW.Therefore, wireless power transfer in tissue using this platform isfeasible. Furthermore, this power level is sufficient to operate highlyefficient, low-power energy harvesting circuits and charge pumps,similar to the ASIC presented here, to output voltages that are suitablefor electrically stimulating nearby neurons and detecting physiologicalconditions using sensors.

Example 6—Tracking of Movement and Temperature Drift of ImplantableDevices

An implantable device was manufactured with on a 50 μm thick polyimideflexible printed circuit board (PCB) with a ultrasonic transducerpiezocrystal (0.75 mm×0.75 mm×0.75 mm) and a custom transistor (0.5mm×0.45 mm) attached to the topside of the board with a conductivesilver paste. Electrical connections between the components are madeusing aluminum wirebonds and conductive gold traces. Exposed goldrecording pads on the bottom of the board (0.2 mm×0.2 mm) are separatedby 1.8 mm and make contact on the nerve or muscle to recordelectrophysiological signals. Recorded signals are sent to thetransistor's input through micro-vias. Additionally, some implants wereequipped with 0.35 mm-wide, 25 mm-long, flexible, compliant leads withtest points for simultaneous measurement of both the voltage across thepiezocrystal and direct wired measurement of the extracellular potentialacross the electrode pair used by the ultrasonic transducer (thisdirect, wired recording of extracellular potential as the ground truthmeasurement is referred to below, which is used as a control for theultrasonically reconstructed data). The entire implant is encapsulatedin a medical grade UV-curable epoxy to protect wirebonds and provideinsulation. A single implantable device measures roughly 0.8 mm×3 mm×1mm. The size of the implants is limited only by our use of commercialpolyimide backplane technology, which is commercially accessible toanyone; relying on more aggressive assembly techniques with in-housepolymer patterning would produce implants not much larger than thepiezocrystal dimensions (yielding a ˜1 mm³ implant).

An external, ultrasonic transceiver board interfaces with theimplantable device by both supplying power (transmit (TX) mode) andreceiving reflected signals (receive (RX) mode). This system is alow-power, programmable, and portable transceiver board that drives acommercially available external ultrasonic transducer (V323-SU, Olympus,Waltham, Mass.). The transceiver board exhibited a de-rated pressurefocus at ˜8.9 mm (FIG. 30A). The XY cross-sectional beam-pattern clearlydemonstrated the transition from the near-field to far-field propagationof the beam, with the narrowest beam at the Rayleigh distance (FIG.30B). The transducer was driven with a 5 V peak-to-peak voltage signalat 1.85 MHz. The measured de-rated peak rarefaction pressure was 14 kPa,resulting in a mechanical index (MI) of 0.01. De-rated spatial pulsepeak average (I_(SPPA)) and spatial peak time average (I_(SPTA)) of 6.37mW/cm² and 0.21 mW/cm² at 10 kHz pulse repetition were 0.0034% and 0.03%of the FDA regulatory limit, respectively (Food and Drug Administration,2008). The transceiver board was capable of outputting up to 32 Vpeak-to-peak and the output pressure increased linearly with the inputvoltage (FIG. 30C).

The entire system was submerged and characterized in a custom-builtwater tank with manual 6 degrees-of-freedom (DOF) linear translationaland rotational stages (Thorlabs Inc., Newton, N.J.). Distilled water wasused as a propagation medium, which exhibits similar acoustic impedanceas tissue, at 1.5 MRayls. For initial calibration of the system, acurrent source (2400-LV, Keithley, Cleveland, Ohio) was used to mimicextracellular signals by forcing electrical current at varying currentdensities through 0.127 mm thick platinum wires (773000, A-M Systems,Sequim, Wash.) immersed in the tank. The neural dust mote was submergedin the current path between the electrodes. As current was appliedbetween the wires, a potential difference arose across the implantelectrodes. This potential difference was used to mimic extracellularelectrophysiological signals during tank testing. To interrogate theneural dust mote, six 540 ns pulses every 100 μs were emitted by theexternal transducer. These emitted pulses reflect off the neural dustmote and produce backscatter pulses back towards the externaltransducer. Reflected backscatter pulses were recorded by the sametransceiver board. The received backscatter waveform exhibits fourregions of interest; these are pulses reflecting from four distinctinterfaces (FIG. 31A): 1) the water-polymer encapsulation boundary, 2)the top surface of the piezoelectric crystal, 3) the piezo-PCB boundary,and 4) the back of the PCB. As expected, the backscatter amplitude ofthe signals reflected from the piezoelectric crystal (second region)changed as a function of changes in potential at the recordingelectrodes. Reflected pulses from other interfaces did not respond tochanges in potential at the recording electrodes. Importantly, pulsesfrom the other non-responsive regions were used as a signal levelreference, making the system robust to motion or heat-induced artifacts(since pulses reflected from all interfaces change with physical orthermal disturbances of the neural dust mote but only pulses from thesecond region change as a function of electrophysiological signals). Ina water tank, the system showed a linear response to changes inrecording electrode potential and a noise floor of −0.18 mVrms (FIG.31B). The overall dynamic range of the system is limited by the inputrange of the transistor and is greater than >500 mV (i.e., there is onlyan incremental change in the current once the transistor is fully on(input exceeds its threshold voltage) or fully off). The noise floorincreased with the measured power drop-off of the beam; 0.7 mm ofmisalignment degraded it by a factor of two (N=5 devices, FIG. 31C).This lateral mis-alignment-induced increase in the noise floorconstitutes the most significant challenge to neural recordings withouta beamsteering system (that is, without the use of an externaltransducer array that can keep the ultrasonic beam focused on theimplanted dust mote and, thus, on-axis). On axis, the implantable deviceconverted incident acoustic power to electrical power across the loadresistance of the piezo with ˜25% efficiency. FIG. 31D plots theoff-axis drop-off of voltage and power at one Rayleigh distance for thetransducer used in this example. Likewise, FIG. 31E plots the change ineffective noise floor as a function of angular misalignment.

Example 7—Digital Communication Link Between Implantable Device andInterrogator

A system including an implantable device and an interrogator having atransducer array is validated with a bench-top setup mimicking anin-vivo environment. Ultrasound coupling gel serves as a tissue phantomdue to its acoustic impedance which is similar to that of targetbiological tissues (approximately 1.5 MRayl). An implantable device witha bulk piezoelectric transducer with direct connections to the twoelectrodes contacting the transducer is placed in the tissue phantom,and the interrogator transducer array is coupled to the gel. Bothelements are attached to precision controlled stages for accuratepositioning. The transducer array is placed 14 mm away from the dustmote, which corresponds to a 18.6 μs round-trip time of flight assumingan acoustic velocity of 1,540 m/s in ultrasound coupling gel. Thetransducer array is excited with six 1.8 MHz, 0-32 V rectangular pulses,and the backscatter signal is digitized with 2000 samples at 17 Msps and12-bits of resolution. For time-domain backscatter inspection, completebackscatter waveforms are filtered in real time on the device and sentto the client through a wired, serial connection. In normal operation,the complete modulation extraction algorithm is applied to thebackscatter data on the device in real-time, compressing the backscattersignal to four bytes. The processed data is transmitted throughBluetooth's SSP protocol to a remote client and streamed through the GUIin real-time.

FIG. 32A shows the filtered backscatter signals collected with thedescribed experimental setup. Signals are collected while the dust motepiezocrystal electrodes are in the shorted and opened configurations.The change in impedance due to the switch activity results in abackscatter peak amplitude that is 11.5 mV greater in the open switchconfiguration, a modulation depth of 6.45%. (FIG. 32B). The longduration of the echo from the mote indicates transducer ringing despitea damping backing layer. While the under-damped transducer systemresponse does spread out the backscatter signal in the time-domain,demodulation is successful as long as the backscatter from the implanteddevice is captured within the ROI.

Using pulse-amplitude-modulated non-return to zero level coding, abackscatter sensor mote is modulated to send a predetermined11-character ASCII message (“hello world”). The modulation of thedevice's acoustic impedance is achieved by shunting the piezoelectrictransducer across a digitally controlled switch where a high levelcorresponds to the open configuration and a low level corresponds to theclosed configuration. FIG. 33 shows the modulated values on thetransducer and the corresponding extracted modulation values of theinterrogator. The absolute value and noise margin of the extractedsignal values depend on a variety of factors such as mote distance,orientation, and size; however, the extracted waveform remainsrepresentative of the modulated signal on the dust mote, varying by alinear scaling factor.

Wirelessly transmitting the extracted backscatter value of theimplantable device modulated by “hello world” demonstrates the device'sreal time communication link with implanted devices. Interrogation of atwo state backscatter system provides a robust demonstration of thesystem's wireless communication link with both an implantable sensor anda remote client. This wireless communication link invites developmentstoward closed-loop neuromodulation systems to connect the brain withexternal devices.

Example 8—Temperature Sensor

This example demonstrates an implantable device comprising a bulkpiezoelectric transducer with a temperature sensor, namely a thermistor.The system uses an interrogator to power the implantable device usingultrasonic waves, and records ultrasonic backscatter from theimplantable device modulated according to the temperature detected bythe sensor. This example demonstrates two sizes of sensors based onavailable components with volumes of 1.45 mm³ and 0.118 mm³. The bulkpiezoelectric transducer can be as small as 700 μm in the largestdimension. The individual sensors are able to resolve ±0.5° C. changesin temperature, suitable for medical diagnostic and monitoring purposes.There is less than 0.3° C. drift in temperature readings over 14 days inphysiological conditions. This approach is also compatible with moresophisticated temperature sensors such as classic proportional toabsolute temperature (PTAT) integrated circuits, as well as digitalbackscatter approaches.

Each implantable device comprises a surface mount thermistor whoseelectrodes are electrically connected to the two terminals of a leadzirconate titanate (PZT) piezoelectric cube with 750 μm edges that areperpendicular to the axis of polarization. The thermistor is a negativetemperature coefficient (NTC) thermistor in order to vary the currentflowing through the two terminals of the piezoelectric crystal as afunction of ambient temperature. Electrical contact and adhesion betweenthe electrode pairs of the thermistor and the piezoelectric crystal areestablished through the application of two distinct, continuous layersof EPO-TEK H20E electrically conductive silver epoxy. PFA-insulatedsilver wire from A-M Systems with an uncoated diameter of 3 mils (5.5mil coated diameter) was attached to each electrode of the thermistorusing silver epoxy in order to measure the voltage harvested by thepiezoelectric cube during water tank characterization. The entireimplantable device, excluding the leads, was then coated with a thinlayer of EPO-TEK OG116-31 UV curable epoxy in order to prevent waterpermeation that could lead to shorts.

In order to assess the backscatter modulation that occurs in thereceived backscatter signal from the implantable device as a function oftemperature, a miniature water tank was made out of polylactic acidusing an additive manufacturing process. The tank was constructed suchthat there is a stage to hold a sensor mote adjacent to a thermocouplethat is used as an input to an Omega Systems CSI32K benchtop PIDcontroller for temperature monitoring and feedback purposes. AnNPT-threaded screw hole was manufactured into the wall of the tank forthe insertion of a heating element into the tank. A second piece of thetank was designed to fit on top of the first component in order to sealthe tank shut and maintain the transducer at one focal distance awayfrom the mote. The base and top of the tank were sealed together usingsilicone, and the top of the tank was sealed with a square of 0.5 milthick PET film in order to thermally isolate the transducer from thetank in an acoustically transparent manner, thereby circumventingartifact superimposition issues that were observed when the transducerwas immersed into the tank at higher water temperatures.

The simplest method to eliminate changes in signal arising from motionartifact in analog backscatter systems like this one is to provide twointerfaces in the implant that produce backscatter: one interface at theresponsive piezoelectric transducer and a second interface at someinvariant material junction. Changes in position or orientation thataffect the entire implant will cause known changes in backscatter fromboth interfaces (i.e., the responsive backscatter and the non-responsivebackscatter), whereas changes in the measured quantity will producechanges only in the backscatter signal from the responsive interface(i.e., the responsive backscatter). The non-responsive region (that is,the region that does not vary relative to temperature) of the receivedbackscatter is determined based on calibration experiments (andtime-of-flight calculations), and changes in the area under the curve ofthis region are compared to the responsive backscatter modulation in thesensor output waveform. In addition, clustering algorithms can be usedto automatically detect a misalignment and to map the changes inbackscatter change to a corresponding change in the measurand (inpreparation). In order to create a non-responsive region of backscatterin the sensor output, a non-responsive reflector, namely a cube ofsilicon, was affixed to the implantable device using UV-curable epoxy.The newly-added cube was electrically isolated from the thermistor inorder to create a fixed region of backscatter in the sensor outputwaveform. The implantable device is shown in FIG. 34A, with relativesizes of the two implantable devices (with volumes of 1.45 mm³ and 0.118mm³) shown in FIG. 34B.

The experimental setup for backscatter characterization of individualimplantable devices is shown in FIG. 35. In order to ensurestandardization in the backscatter collection protocol and to maximizethe magnitude of the expected response, the implantable devices werealigned to the ultrasonic beam produced by the commercially availablesingle element transducer (V323-SU, Olympus) as assessed by themaximization of the peak voltage being harvested by the piezoelectriccrystal on the implantable device. The implantable devices wereinterrogated at a frequency of 1.8 MHz, and the backscatter was sampledat 1 kHz, although lower sampling rates are possible. The transducer'sfocal length is 0.9 cm; the distance between the transducer and themotes was set so that the motes were at the focus point. The temperaturewithin the tank was tightly regulated using the benchtop PID controllerand varied from 34.5° C. to 45.5° C. in increments of 0.5° C. At eachtemperature value, ten backscatter waveforms were recorded using anAgilent Tech InfiniiVision DSO-X3024A digital storage oscilloscope. Itwas observed that the time of flight of the ultrasonic backscatterincreases as a function of temperature due to the change of acousticvelocity in water. Thus, the waveform features of interest weretemporally aligned to a reference waveform for each backscatter dataset.The reference waveform was selected to be the backscatter waveform at44.5° C. for each run. The index of maximum change in backscattervoltage with respect to the reference waveform was found for each trialwaveform, the signal was then rectified, filtered and integrated overspecified time indices of interest where the maximum change inbackscatter amplitude occurs. The same integration bounds were utilizedfor every temperature that was tested for an individual mote, and theobtained integrals were then normalized with respect to the integralobtained from the reference measurement.

In order to verify that the effects observed in backscatter modulationare not due to changes in external transducer properties as a functionof temperature, backscatter tests were conducted in an empty water tankover the temperatures of interest. No significant temperature effects onthe received backscatter waveforms were found under these testconditions. Also assessed was the long term drift of the thermistors.Five Panasonic ERT-J1VR682J thermistors were mounted on individualprototyping printed circuit boards (Chip Quik Inc., DC0603T), solderedto leads and covered with UV-curable epoxy. Thermistors were then placedin a beaker containing deionized water; a closed loop temperaturecontrol system consisting of a 55 W compact immersion heater(McMaster-Carr, 4668T51), an Omega Systems CSI32K benchtop PIDcontroller and a thermocouple were used to keep the water temperature at45.5° C. Resistance values were measured from each thermistor atapproximately 24-hour intervals over 14 days and percent change in theaverage value was calculated for each thermistor.

The implantable devices include a 0201 SMD packaged thermistor(Panasonic ERT-JZET202J) and a PZT piezocrystal having an edge length of400 μm (FIG. 34B, top), or a 0603 thermistor and a PZT piezocrystalhaving an edge length of 750 μm (FIG. 34B, bottom).

FIG. 36 shows a typical backscatter profile from an implantable devicecomprising both a non-responsive reflector and a bulk piezoelectrictransducer connected to a thermistor. Region 1 arises from thenon-responsive reflector and region 2 arises from the responsivepiezoelectric transducer. Both regions vary with displacement androtation while only the responsive region varies with temperaturechanges, as shown.

A single implantable device with an temperature sensor is capable ofproducing a monotonically varying temperature-dependent change inbackscatter for physiologically-relevant temperatures with a 0.5° C.precision, as shown in FIG. 37. Over 14 days, the maximum deviation inthe mean recordings for a thermistor was found to be 34Ω. TheSteinhart-Hart equation models the relationship between temperature andresistance for an NTC thermistor:

R=R ₀ exp[−β(1/T ₀−1/T)]

where R is the measured resistance value at temperature T. For the used0603 thermistors, the decay parameter β is 4250 K⁻¹, and R₀ was reportedto be 6.8 kΩ for an initial temperature T₀=298 K. The temperature changethat corresponds to a change in resistance can be found by applying theSteinhart-Hart equation twice and rearranging:

T ₂ =βT ₀/[T ₀ ln(ΔR/R ₀+exp[−β(1/T ₀−1/T ₁)])+β]

where ΔR is the change in resistance values R₂−R₁ at temperatures T₂ andT₁ respectively. It was found that the change in resistance of 34Ωcorresponds to a temperature change of 0.296 K. This temperature changeis within the measurement error for the PID controller.

This example demonstrates that the implantable device with a thermalsensor in an ultrasonically addressable system with a miniaturizedultrasonic transducer as small as 700 μm in their largest dimensionusing commercially available components. This method does not depend onempirical heat exchange models for the determination of temperaturemeasurements, and as such could become a useful tool in deep tissuetemperature measurements. For completeness, it was verified thatthermistors, which are a skin temperature acquisition standard inclinical medicine, do not exhibit significant drift when exposed tophysiological temperatures over extended periods of time. Individualimplantable devices were able to resolve changes in temperature withgood precision at 1 cm from the transducer, which is significant formedical diagnostic and monitoring purposes. Lastly, it was demonstratedthat the implantable devices can be assembled using smaller readilyavailable components to create a fully sub-millimeter sensor. Given theability to penetrate centimeters deep into tissue, this approachprovides a straightforward way to sense deep-tissue temperature.

1-30. (canceled)
 31. An implantable device, comprising: a sensorconfigured to detect a physiological signal; and an ultrasonictransducer with a longest dimensional length of 5 mm or less, theultrasonic transducer configured to receive ultrasonic waves that powerthe implantable device, receive a current modulated based on thephysiological signal detected by the sensor, and emit aphysiological-signal-dependent ultrasonic backscatter based on thecurrent received by the ultrasonic transducer.
 32. The implantabledevice of claim 31, wherein the ultrasonic backscatter encodes adigitized signal.
 33. The implantable device of claim 31, wherein theultrasonic transducer is configured to receive ultrasonic waves thatpower the implantable device.
 34. The implantable device of claim 33,wherein the ultrasonic transducer is configured to receive theultrasonic waves from an interrogator comprising one or more ultrasonictransducers.
 35. The implantable device of claim 31, wherein theultrasonic transducer is a bulk piezoelectric transducer, apiezoelectric micro-machined ultrasonic transducer (PMUT) or acapacitive micro-machined ultrasonic transducer (CMUT).
 36. Theimplantable device of claim 31, wherein the implantable device is 5 mmor less in length in the longest dimension.
 37. The implantable deviceof claim 31, wherein the volume of the implantable device is about 5 mm³or less.
 38. The implantable device of claim 31, wherein the implantabledevice further comprises an integrated circuit.
 39. The implantabledevice of claim 38, wherein the integrated circuit comprises a powercircuit.
 40. The implantable device of claim 38, wherein the integratedcircuit comprises a driver configured to provide a current to thesensor.
 41. The implantable device of claim 38, wherein the integratedcircuit comprises a front end configured to receive a signal from thesensor.
 42. The implantable device of claim 38, wherein the integratedcircuit comprises a digital circuit.
 43. The implantable device of claim42, wherein the digital circuit is configured to operate a modulationcircuit.
 44. The implantable device of claim 43, wherein the digitalcircuit is configured to transmit a digitized signal to the modulationcircuit, wherein the digitized signal is based on the detectedphysiological signal.
 45. The implantable device of claim 42, whereinthe integrated circuit comprises a memory that stores one or moreprograms for operating the implantable device.
 46. The implantabledevice of claim 41, wherein the digital circuit comprises amicrocontroller.
 47. The implantable device of claim 41, wherein thedigital circuit comprises a finite state machine.
 48. The implantabledevice of claim 31, wherein the implanted device is at least partiallyencapsulated by a biocompatible material.
 49. The implantable device ofclaim 31, wherein the implantable device comprises two or more sensors.50. A system, comprising: the implantable device of claim 31; and aninterrogator comprising one or more ultrasonic transducers configured totransmit the ultrasonic waves that power the implantable device, andreceive the ultrasonic backscatter from the implantable device.